Arylsulfonamido-substituted hydroxamic acids

ABSTRACT

The invention relates to the compounds of formula I ##STR1## pharmaceutically acceptable prodrug derivatives and pharmaceutically acceptable salts thereof; methods for preparation thereof; pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinase and of treating matrix-degrading metalloproteinase dependent conditions in mammals using such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of applicationSer. No. 08/265,296 filed Jun. 24, 1994, now allowed which is acontinuation-in-part application of application Ser. No. 8/001,136 filedJan. 6, 1993, now U.S. Pat. No. 5,455,258.

SUMMARY OF THE INVENTION

The present invention relates to novel arylsulfonamido-substitutedhydroxamic acids, as matrix metalloproteinase inhibitors, methods forpreparation thereof, pharmaceutical compositions comprising saidcompounds, a method of inhibiting matrix-degrading metalloproteinasesand a method of treating matrix metalloproteinase dependent diseases orconditions in mammals which are responsive to matrix metalloproteaseinhibition, using such compounds or pharmaceutical compositionscomprising such compounds of the invention.

Matrix-degrading metalloproteinases, such as gelatinase, stromelysin andcollagenase, are involved in tissue matrix degradation (e.g. collagencollapse) and have been implicated in many pathological conditionsinvolving abnormal connective tissue and basement membrane matrixmetabolism, such as arthritis (e.g. osteoarthritis and rheumatoidarthritis), tissue ulceration (e.g. corneal, epidermal and gastriculceration), abnormal wound healing, periodontal disease, bone disease(e.g. Paget's disease and osteoporosis), tumor metastasis, tumorprogression or invasion, as well as HIV-infection (as reported in J.Leuk. Biol. 52 (2): 244-248, 1992), atherosclerosis and restenosis inangioplasty.

Macrophage metalloelastase is a further matrix-degradingmetalloproteinase which is involved in the degradation of elastin andhas been implicated in pathological conditions, e.g. pulmonary disorderssuch as emphysema.

The compounds of the invention are inhibitors of stromelysin, gelatinaseand/or collagenase activity, inhibit matrix degradation and are usefulfor the treatment of gelatinase, stromelysin and collagenase dependentpathological conditions in mammals, such as those cited above, includingrheumatoid arthritis, osteoarthritis, tumor metastasis, tumorprogression or invasion, periodontal disease, as well as the progressionof HIV-infection and associated disorders, atherosclerosis,osteoporosis, and restenosis associated with angioplasty.

The compounds of the invention are also inhibitors of macrophageelastase, inhibit elastin degradation and are useful for the treatmentof bronchial disorders, such as emphysema.

Ocular applications of the compounds of the invention include thetreatment of corneal ulcerations, pterygium, keratitis, keratoconus,open angle glaucoma, retinopathies, and also their use in conjunctionwith refractive surgery (laser or incisional) to minimize adverseeffects.

Certain metalloproteinase inhibitors have been reported to also inhibitthe production and release of tumor necrosis factors (TNF) e.g. TNF-αwhich is an important mediator of inflammation. Thus, compounds of theinvention are potential anti-inflammatory agents in mammals.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the compounds of formula I ##STR2##

(a) wherein

Ar is carbocyclic or heterocyclic aryl;

R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclicaryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclicaryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃ -C₇ -cycloalkyl, C₃-C₇ -cycloalkyl-lower alkyl, (oxa or thia)-C₃ -C₆ -cycloalkyl, [(oxa orthia)-C₃ -C₆ -cycloalkyl]-lower alkyl, hydroxy-lower alkyl,acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio,sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-loweralkylamino)-lower alkyl, acylamino-lower alkyl, (N-loweralkyl-piperazino or N-carbocyclic or heterocyclic aryl-loweralkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino,piperidino, pyrrolidino, piperidyl or N-lower alkylpiperidyl)-loweralkyl;

R₁ is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclicaryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclicaryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃ -C₁₀ -cycloalkyl,C₃ -C₇ -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-loweralkyl, lower alkoxy-lower alkyl, (carbocyclic or heterocyclicaryl)-lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl orsulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-loweralkyl, (N-lower alkyl-piperazino or N-carbocyclic or heterocyclicaryl-lower alkylpiperazino)-lower alkyl, (morpholino, thiomorpholino,piperidino, pyrrolidino, piperidyl, N-acyl or N-loweralkylpiperidyl)-lower alkyl, acylamino-lower alkyl, pipefidyl,(morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acylor N-lower alkylpiperidyl)-(hydroxy or lower alkoxy) lower alkyl,pyrrolidinyl, hexahydroazepinyl, N-lower alkyl orN-acyl(hexahydroazepinyl, pipefidyl or pyrrolidinyl), C₅ -C₁₀-oxacycloalkyl, C₅ -C₁₀ -thiacycloalkyl, (hydroxy- or oxo-) C₅ -C₁₀-cycloalkyl, (hydroxy- or oxo-) C₅ -C₁₀ -thiacycloalkyl, (hydroxy- oroxo-) C₅ -C₁₀ -oxacycloalkyl, (amino, mono- or dialkylamino oracylamino)-C₅ -C₁₀ -cycloalkyl, 2-oxo(pyrrolidinyl, piperidyl orhexahydroazepinyl), (carbocyclic or heterocyclic aryl)-(thio, sulfinylor sulfonyl)-lower alkyl;

R₂ is hydrogen or lower alkyl;

(b) or wherein R and R₁ together with the chain to which they areattached form a 1,2,3,4-tetrahydro-isoquinoline, piperidine,oxazolidine, thiazolidine or pyrrolidine ring, each unsubstituted orsubstituted by lower alkyl; and Ar and R₂ have meaning as defined under(a);

(c) or wherein R₁ and R2 together with the carbon atom to which they areattached form a ring system selected from C₃ -C₇ -cycloalkane which isunsubstituted or substituted by lower alkyl; oxa-cyclohexane,thia-cyclohexane, indane, tetratin, piperidine or piperidine substitutedon nitrogen by acyl, lower alkyl, carbocyclic or heterocyclic aryl-loweralkyl, (carboxy, esterified or amidated carboxy)-lower alkyl or by loweralkylsulfonyl; and Ar and R have meaning as defined under (a);

pharmaceutically acceptable prodrug derivatives thereof; andpharmaceutically acceptable salts thereof;

further to a process for the preparation of these compounds, topharmaceutical compositions comprising these compounds, to the use ofthese compounds for the therapeutic treatment of the human or animalbody or for the manufacture of a pharmaceutical composition.

The compounds of formula I defined under (b) above can be represented byformula Ia ##STR3## wherein X represents methylene or 1,2-ethylene eachunsubstituted or substituted by lower alkyl, or X represents oxygen,sulfur, or 1,2-phenylene; and Ar and R₂ have meaning as defined above.

The compounds of formula I defined under (c) above can be represented byformula Ib ##STR4## wherein Y is a direct bond, C₁ -C₄ -straight chainalkylene optionally substituted by lower alkyl, CH₂ OCH₂, CH₂ SCH₂,1,2-phenylene, CH₂ -1,2-phenylene or CH₂ N(R₆)--CH₂ in which R₆represents hydrogen, lower alkanoyl, di-lower alkylamino-lower alkanoyl,aroyl, carbocyclic aryl-lower alkanoyl, lower alkyl, carbocyclic orheterocylic aryl-lower alkyl, (carboxy, esterified or amidatedcarboxy)-lower alkyl or lower alkylsulfonyl; and Ar and R have meaningas defined above.

A preferred embodiment of the compounds of formula Ib relates to thecompounds of formula Ic ##STR5## in which Y' represents oxygen, sulfur,a direct bond, methylene or methylene substituted by lower alkyl, or NR₆; R₆ represents hydrogen, lower alkanoyl, di-lower alkylamino-loweralkanoyl, carbocyclic aryl-lower alkanoyl, lower alkyl, carbocyclic orheterocyclic aryl-lower alkyl, (carboxy, esterified or amidatedcarboxy)-lower alkyl or lower alkylsulfonyl; Ar and R have meaning asdefined above; pharmaceutically acceptable prodrug derivatives; andpharmaceutically acceptable salts thereof.

Preferred are said compounds of formula I, Ia, Ib and Ic wherein Ar ismonocyclic carbocyclic aryl such as phenyl or phenyl mono-, di- ortri-substituted by C₁ -C₁₀ -alkoxy, hydroxy, carbocyclic or heterocyclicaryl-lower alkoxy, C₃ -C₇ -cycloalkyl-lower alkoxy, (lower alkyl,carbocyclic or heterocyclic aryl-lower alkyl or C₃ -C₇ -cycloalkyl-loweralkyl)-thio, lower alkyloxy-lower alkoxy, halogen, lower alkyl, cyano,nitro, trifluoromethyl, lower alkyl-(sulfinyl or sulfonyl), amino ormono- or di-lower alkylamino; or Ar is phenyl substituted on adjacentcarbon atoms by C₁ -C₂ -alkylenedioxy or oxy-C₂ -C₃ -alkylene; or Ar isheterocyclic monocyclic aryl such as thienyl or thienyl substituted bylower alkyl; the other symbols have meaning as defined; pharmaceuticallyacceptable prodrug derivatives thereof; and pharmaceutically acceptablesalts thereof.

Further preferred are the compounds of formula I

(a) wherein Ar is phenyl which is unsubstituted or mono-, di- ortri-substituted by C₁ -C₁₀ -alkoxy, hydroxy; phenyl-lower alkoxy whereinphenyl is unsubstituted or substituted by lower alkyl, lower alkoxy,halogen or trifluoromethyl; heterocyclic aryl-lower alkoxy whereinheterocyclic aryl is selected from pyridyl, tetrazolyl, triazolyl,thiazolyl, thienyl, imidazolyl and quinolinyl, each unsubstituted ormono- or disubstituted by lower alkyl or halogen; or Ar is phenylsubstituted by C₃ -C₇ -cycloalkyl-lower alkoxy, (lower alkyl,phenyl-lower alkyl or C₃ -C₇ -cycloalkyl-lower alkyl)-thio, loweralkyloxy-lower alkoxy, halogen, lower alkyl, cyano, nitro,trifluoromethyl, lower alkyl-(sulfinyl or sulfonyl), amino, mono- ordi-lower alkylamino; or Ar is phenyl substituted on adjacent carbonatoms, by C₁ -C₂ -alkylenedioxy or oxy-C₂ -C₃ -alkylene; or Ar isthienyl, isoxazolyl or thiazolyl each of which is unsubstituted or mono-or di-substituted by lower alkyl;

R is hydrogen, lower alkyl, phenyl-lower alkyl wherein phenyl isunsubstituted or substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; phenyl which is unsubstituted or mono-, di- ortri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl, cyano,nitro, trifluoromethyl, lower alkyl-(thio, sulfinyl or sulfonyl), amino,mono- or di-lower alkylamino or, on adjacent carbon atoms, by C₁ -C₂-alkylenedioxy or oxy-C₂ -C₃ -alkylene; or a heterocyclic aryl radicalselected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl,imidazolyl and quinolinyl, each unsubstituted or mono- or disubstitutedby lower alkyl or halogen; biphenylyl which is unsubstituted orsubstituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl orcyano; biphenylyl-lower alkyl wherein biphenylyl is unsubstituted orsubstituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl orcyano; (pyridyl, thienyl, quinolinyl or thiazolyl)-lower alkyl,trifluoromethyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-lower alkyl,(oxa or thia)-C₃ -C₆ -cycloalkyl, [(oxa or thia)-C₃ -C₆-cycloalkyl]-lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-loweralkyl, lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl orsulfonyl)-lower alkyl, (amino, mono- or di-lower alkylamino)-loweralkyl, lower alkanoylamino-lower alkyl, (N-lower alkyl-piperazino orN-phenyl-lower alkylpiperazino)-lower alkyl or (morpholino,thiomorpholino, piperidino, pyrrolidino, pipefidyl or N-loweralkylpiperidyl)-lower alkyl;

R₁ is hydrogen; lower alkyl; phenyl-lower alkyl wherein phenyl isunsubstituted or substituted by lower alkyl, lower alkoxy, halogen,trifluoromethyl or, on adjacent carbon atoms, by C₁ -C₂ -alkylenedioxyor oxy-C₂ -C₃ -alkylene; phenyl which is unsubstituted or substituted bylower alkyl, lower alkoxy, halogen or trifluoromethyl; pyridyl; thienyl,biphenylyl; biphenylyl-lower alkyl; heterocyclic aryl-lower alkylwherein heterocyclic aryl is selected from thiazolyl, pyrazolyl,pyridyl, imidazolyl and tetrazolyl each unsubstituted or substituted bylower alkyl; trifluoromethyl; C₃ -C₇ -cycloalkyl, C₃ -C₇-cycloalkyl-lower alkyl; hydroxy-lower alkyl; lower alkanoyloxy-loweralkyl; lower alkoxy-lower alkyl; (phenyl or pyridyl)-lower alkoxy-loweralkyl; lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl; (amino,mono- or di-lower alkylamino)-lower alkyl; (N-lower alkyl-piperazino orN-phenyl-lower alkylpiperazino)-lower alkyl; (morpholino,thiomorpholino, piperidino, pyrrolidino, pipefidyl or N-loweralkylpiperidyl)-lower alkyl; lower alkanoylamino-lower alkyl; R₃-CONH-lower alkyl wherein R₃ represents (di-lower alkylamino, N-loweralkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino orN-alkylpiperidyl)-lower alkyl; pipefidyl; pyrrolidinyl;hexahydroazepinyl; N-lower alkyl- or N-acyl-(hexahydroazepinyl,piperidyl or pyrrolidinyl); C₅ -C₁₀ -oxacycloalkyl; C₅ -C₁₀-thiacycloalkyl; (hydroxy- or oxo-) C₅ -C₁₀ -cycloalkyl; (hydroxy- oroxo-) C₅ -C₁₀ -thiacycloalkyl; (hydroxy- or oxo-) C₅ -C₁₀-oxacycloalkyl; (amino, mono- or dialkylamino or lower alkanoylamino)-C₅-C₁₀ -cycloalkyl; phenyl-thio-lower alkyl wherein phenyl isunsubstituted or substituted by lower alkyl, lower alkoxy, halogen,trifluoromethyl, or, on adjacent carbon atoms, by C₁ -C₂ -alkylenedioxyor oxy-C₂ -C₃ -alkylene; heterocyclic aryl-thio-lower alkyl whereinheterocyclic aryl is selected from thiazolyl, pyrazolyl, pyridyl,imidazolyl, thienyl and furanyl, each unsubstituted or substituted bylower alkyl;

R₂ is hydrogen or lower alkyl;

(b) or wherein R and R₁ together with the chain to which they areattached form a 1,2,3,4-tetrahydro-isoquinoline, piperidine,oxazolidine, thiazolidine or pyrrolidine ting, each unsubstituted ormono- or di-substituted by lower alkyl; and Ar and R₂ have meaning asdefined under (a);

(c) or wherein R₁ and R₂ together with the carbon atom to which they areattached form a ring system selected from C₃ -C₇ -cycloalkane which isunsubstituted or substituted by lower alkyl; oxa-cyclohexane,thia-cyclohexane, indane, tetralin and piperidine which is unsubstitutedor substituted on nitrogen by lower alkanoyl, di-lower alkylamino-loweralkanoyl, lower alkoxycarbonyl, (morpholino, thiomorpholino orpiperidino)-carbonyl, lower alkyl, (phenyl or pyridyl)-lower alkyl,(carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, aminocarbonyl ormono- or di-lower alkylaminocarbonyl)-lower alkyl or by loweralkylsulfonyl; and Ar and R have meaning as defined under (a);

a pharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.

Especially preferred are the compounds of formula I

(a) wherein Ar is phenyl which is unsubstituted or mono-, di- ortri-substituted by C₁ -C₇ -alkoxy, hydroxy, phenyl-lower alkoxy, C₃ -C₇-cycloalkyl-lower alkoxy, lower alkyloxy-lower alkoxy, halogen, loweralkyl, cyano, nitro, trifluoromethyl, lower alkyl-(sulfinyl orsulfonyl), amino, mono- or di-lower alkylamino or, on adjacent carbonatoms, by C₁ -C₂ -alkylenedioxy or oxy-C₂ -C₃ -alkylene; or Ar isthienyl, isoxazolyl or thiazolyl each of which is unsubstituted or mono-or di-substituted by lower alkyl;

R is hydrogen; lower alkyl, phenyl-lower alkyl; phenyl which isunsubstituted or mono-, di- or tri-substituted by lower alkoxy, hydroxy,halogen, lower alkyl, trifluoromethyl, or, on adjacent carbon atoms, byC₁ -C₂ -alkylenedioxy or oxy-C₂ -C₃ -alkylene; a heterocyclic arylradical selected from pyridyl, thiazolyl and quinolinyl, eachunsubstituted or mono- or disubstituted by lower alkyl; biphenylyl;biphenylyl-lower alkyl; (pyridyl or thienyl)-lower alkyl;trifluoromethyl; C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-lower alkyl;(oxa or thia)-C₃ -C₆ -cycloalkyl, [(oxa or thia)-C₃ -C₆-cycloalkyl]-lower alkyl; hydroxy-lower alkyl; (N-lower alkyl-piperazinoor N-phenyl-lower alkylpiperazino)-lower alkyl or (morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl or N-loweralkylpiperidyl)-lower alkyl; R₁ is hydrogen; lower alkyl; phenyl-loweralkyl wherein phenyl is unsubstituted or substituted by lower alkyl,lower alkoxy, halogen, trifluoromethyl or, on adjacent carbon atoms, byC₁ -C₂ -alkylenedioxy; biphenylyl-lower alkyl; heterocyclic aryl-loweralkyl wherein heterocyclic aryl is selected from thiazolyl, pyrazolyl,pyridyl, imidazolyl and tetrazolyl each unsubstituted or substituted bylower alkyl; C₃ -C₁₀ -cycloalkyl; C₃ -C₇ -cycloalkyl-lower alkyl;hydroxy-lower alkyl, (phenyl or pyridyl)-lower alkoxy-lower alkyl; loweralkyl-(thio, sulfinyl or sulfonyl)-lower alkyl; (amino, mono- ordi-lower alkylamino)-lower alkyl; (N-lower alkyl-piperazino orN-phenyl-lower alkyl-piperazino)-lower alkyl; (morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl or N-loweralkylpiperidyl)-lower alkyl; lower alkanoylamino-lower alkyl; R₃-CONH-lower alkyl wherein R₃ represents (di-lower alkylamino, N-loweralkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino orN-alkylpiperidyl)-lower alkyl piperidyl; pyrrolidinyl;hexahydroazepinyl; N-lower alkyl- or N-acyl-(hexahydroazepinyl,piperidyl or pyrrolidinyl); C₅ -C₁₀ -oxacycloalkyl; C₅ -C₁₀-thiacycloalkyl; (hydroxy- or oxo-) C₅ -C₁₀ -cycloalkyl; (hydroxy- oroxo-) C₅ -C₁₀ -thiacycloalkyl; (hydroxy- or oxo-) oxacycloalkyl; (amino,mono- or dialkylamino or lower alkanoylamino)-C₅ -C₁₀ -cycloalkyl;phenyl-thio-lower alkyl wherein phenyl is unsubstituted or substitutedby lower alkyl, lower alkoxy, halogen or trifluoromethyl; heterocyclicaryl-thio-lower alkyl wherein heterocyclic aryl is selected from thienyland furanyl, each unsubstituted or substituted by lower alkyl;

R₂ is hydrogen or lower alkyl;

(b) or wherein R and R₁ together with the chain to which they areattached form a thiazolidine or pyrrolidine ring, each unsubstituted ormono- or di-substituted by lower alkyl; and Ar and R₂ have meaning asdefined under (a);

(c) or wherein R₁ and R₂ together with the carbon atom to which they areattached form a ring system selected from C₃ -C₇ -cycloalkane which isunsubstituted or substituted by lower alkyl; oxa-cyclohexane;thia-cyclohexane; and piperidine which is unsubstituted or substitutedon nitrogen by lower alkanoyl, di-lower alkylamino-lower alkanoyl, loweralkoxycarbonyl, (morpholino, thiomorpholino or piperidino)-carbonyl,lower alkyl, (phenyl or pyridyl)-lower alkyl, (carboxy, loweralkoxycarbonyl, aminocarbonyl or mono- or di-loweralkylaminocarbonyl)-lower alkyl or by lower alkylsulfonyl; and Ar and Rhave meaning as defined under (a);

a pharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.

A particular embodiment of the invention relates to the compounds offormula II ##STR6##

wherein

R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclicaryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclicaryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃ -C₇ -cycloalkyl, C₃-C₇ -cycloalkyl-lower alkyl, (oxa or thia)-C₃ -C₆ -cycloalkyl, [(oxa orthia)-C₃ -C₆ -cycloalkyl]-lower alkyl, hydroxy-lower alkyl,acyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-(thio,sulfinyl or sulfonyl)-lower alkyl, (amino, mono- or di-loweralkylamino)-lower alkyl, acylamino-lower alkyl, (N-loweralkyl-piperazino or N-carbocyclic or heterocyclic aryl-loweralkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino,piperidino, pyrrolidino or N-lower alkylpiperidyl)-lower alkyl;

R₁ is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclicaryl, heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclicaryl-lower alkyl, mono- or poly-halo-lower alkyl, C₅ -C₈ -cycloalkyl, C₅-C₇ -cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl,lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-loweralkyl, (amino, mono- or di-lower alkylamino)-lower alkyl, (N-loweralkyl-piperazino or N-carbocyclic or heterocyclic aryl-loweralkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino,pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl,piperidyl, N-lower alkylpiperidyl, or acylamino-lower alkyl representedby R₃ -CONH-lower alkyl, pyrrolidinyl, hexahydroazepinyl or N-loweralkyl (pyrrolidinyl or hexahydroazepinyl), C₅ -C₇ -oxacycloalkyl, C₅ -C₇-thiacycloalkyl, hydroxy or oxo-cyclohexyl, (amino, mono- or di-loweralkylamino) cyclohexyl or 2-oxohexahydroazepinyl; phenyl-thio-loweralkyl wherein phenyl is unsubstituted or substituted by lower alkyl;heterocyclic aryl-thio-lower alkyl wherein heterocyclic aryl is selectedfrom thienyl and furanyl, each unsubstituted or substituted by loweralkyl;

R₂ is hydrogen;

R₃ in R₃ -CONH-lower alkyl is lower alkyl, carbocyclic or heterocyclicaryl, di-lower alkylamino, N-lower alkylpiperazino, morpholino,thiomorpholino, piperidino, pyrrolidino, N-alkylpiperidyl, or (di-loweralkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino,piperidino, pyrrolidino, pyridyl or N-lower alkylpiperidyl)-lower alkyl;

R₄ is hydrogen, lower alkoxy, hydroxy, carbocyclic or heterocyclicaryl-lower alkoxy, lower alkylthio or carbocyclic or heterocyclicaryl-lower alkylthio, lower alkyloxy-lower alkoxy, halogen,trifluoromethyl, lower alkyl, nitro or cyano;

R₅ is hydrogen, lower alkyl or halogen;

or R₄ and R₅ together on adjacent carbon atoms represent methylenedioxy,ethylenedioxy, oxyethylene or oxypropylene;

or a pharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.

Another preferred embodiment of the invention relates to the compoundsof formula II wherein R and R₁ together with the chain to which they areattached form an 1,2,3,4-tetrahydro-isoquinoline, piperidine,thiazolidine or pyrrolidine ring; and R₂, R₄ and R₅ have meaning asdefined above; pharmaceutically acceptable prodrug derivatives; andpharmaceutically acceptable salts thereof. Such compounds correspond tocompounds of formula Ia wherein Ar is optionally substituted phenyl asdefined above.

Another preferred embodiment of the invention relates to the compoundsof formula II wherein R₁ and R₂ together with the carbon atom to whichthey are attached form a ring system selected from cyclohexane,cyclopentane, oxacyclohexane, thiacyclohexane, indane, tetralin,piperidine or piperidine substituted on nitrogen by acyl, lower alkyl,carbocyclic or heterocyclic aryl-lower alkyl or by lower alkylsulfonyl;and R, R₄ and R₅ have meaning as defined above; pharmaceuticallyacceptable prodrug derivatives; and pharmaceutically acceptable saltsthereof. Such compounds correspond to compounds of formula Ib wherein Aris optionally substituted phenyl as defined above.

Particularly preferred are the compounds of formula III ##STR7##

wherein R represents lower alkyl, trifluoromethyl, C₅ -C₇ -cycloalkyl,(oxa or thia)-C₄ -C₅ -cycloalkyl, biaryl, carbocyclic monocyclic aryl orheterocyclic monocyclic aryl; R₁ represents hydrogen, lower alkyl, C₅-C₈ -cycloalkyl, monocyclic carbocyclic aryl, carbocyclic aryl-loweralkyl, heterocyclic aryl-lower alkyl, lower alkoxy-lower alkyl,hydroxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-loweralkyl, di-lower alkylamino-lower alkyl, (N-lower alkylpiperazino,morpholino, thiomorpholino, piperidino or pyrrolidino)-lower alkyl, C₅-C₇ -oxacycloalkyl, (hydroxy, oxo or di-lower alkylamino) cyclohexyl, R₃-CONH-lower alkyl, phenyl-thio-lower alkyl wherein phenyl isunsubstituted or substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl, heterocyclic aryl-thio-lower alkyl wherein heterocyclicaryl is selected from thiazolyl, pyridyl, imidazolyl, thienyl andfuranyl, each unsubstituted or substituted by lower alkyl; R₃ representslower alkyl, carbocyclic aryl, heterocyclic aryl, di-lower alkylamino,N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino,pyrrolidino, N-alkylpiperidyl, or (all-lower alkylamino, N-loweralkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino orN-alkylpiperidyl)-lower alkyl; R₄ represents lower alkoxy or carbocyclicor heterocyclic aryl-lower alkoxy; or a pharmaceutically acceptableprodrug derivative thereof: or a pharmaceutically acceptable saltthereof.

Further preferred are compounds of formula III wherein R representsmonocyclic carbocyclic aryl or monocyclic heterocyclic aryl; R₁ and R₄have meaning as defined above; pharmaceutically acceptable prodrugderivatives; and pharmaceutically acceptable salts thereof.

More particularly preferred are said compounds of formula III wherein Rrepresents heterocyclic monocyclic aryl selected from tetrazolyl,triazolyl, thiazolyl, imidazolyl and pyridyl, each unsubstituted orsubstituted by lower alkyl; or R represents phenyl or phenyl substitutedby lower alkyl, lower alkoxy, halogen or trifluoromethyl; R₁ representslower alkyl, cyclohexyl, 2- or 3-tetrahydrofuranyl,(phenyl-, thienyl- orfuranyl-)thiomethyl, or R₃ -CONH-lower alkyl wherein R₃ represents(di-lower alkylamino, N-lower alkylpiperazino, morpholino,thiomorpholino, piperidino, pyrrolidino or N-alkylpiperidyl)-loweralkyl; and R₄ represents lower alkoxy or phenyl-lower alkoxy; or apharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.

A further preferred embodiment relates to said compounds of formula IIIwherein R represents 2-, 3- or 4-pyridyl or phenyl; R₁ represents C₁ -C₄-alkyl, cyclohexyl, 2- or 3-tetrahydrofuranyl, or R₃ -CONH-C₁ -C₄ -alkylwherein R₃ represents di-C₁ -C₄ -alkylamino-C₁ -C₄ -lower alkyl; and R₄represents lower alkoxy; or a pharmaceutically acceptable prodrugderivative thereof; or a pharmaceutically acceptable salt thereof.

Particularly preferred are said compounds of formula III wherein Rrepresents 3-pyridyl or 4-pyridyl; R₁ represents isopropyl, cyclohexylor 2-tetrahydrofuranyl; and R₄ represents lower alkoxy; or apharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to compounds of Formula IIIwherein R represents pyridyl, pyridyl substituted by lower alkyl,phenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R₁ represents (phenyl-, thienyl- or furanyl-) thio-C₁-C₄ -alkyl; and R₄ represents lower alkoxy; or a pharmaceuticallyacceptable prodrug derivative thereof; or a pharmaceutically acceptablesalt therof.

Further preferred are said compounds of Formula III wherein R representsphenyl or phenyl substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R₁ represents (phenyl)-thiomethyl,(2-thienyl)-thiomethyl or (2-furanyl)-thiomethyl; and R₄ representslower alkoxy; or a pharmaceutically acceptable prodrug derivativethereof; or a pharmaceutically acceptable salt thereof.

The invention relates especially to the specific compounds described inthe examples, pharmaceutically acceptable prodrug derivatives thereofand pharmaceutically acceptable salts thereof, and in particular to thespecific compounds described in the examples and pharmaceuticallyacceptable salts thereof.

Pharmaceutically acceptable prodrug derivatives are those that may beconvertible by solvolysis or under physiological conditions to the freehydroxamic acids of the invention and represent such hydroxamic acids inwhich the CONHOH group is derivatized in form of an O-acyl or anoptionally substituted O-benzyl derivative. Preferred are the optionallysubstituted O-benzyl derivatives. The compounds of the inventiondepending on the nature of the substituents, possess one or moreasymmetric carbon atoms. The resulting diastereoisomers and enantiomersare encompassed by the instant invention.

Preferred are the compounds of the invention wherein the asymmetriccarbon in the above formulae (to which are attached R₁ and/or R₂)corresponds to that of a D-aminoacid precursor and is assigned the(R)-configuration.

The general definitions used herein have the following meaning withinthe scope of the present invention, unless otherwise specified.

The term "lower" referred to above and hereinafter in connection withorganic radicals or compounds respectively defines such as branched orunbranched with up to and including 7, preferably up to and including 4and advantageously one or two carbon atoms.

A lower alkyl group is branched or unbranched and contains 1 to 7 carbonatoms, preferably 1-4 carbon atoms, and represents for example methyl,ethyl, propyl, butyl, isopropyl or isobutyl.

A lower alkoxy (or alkyloxy) group preferably contains 1-4 carbon atoms,advantageously 1-3 carbon atoms, and represents for example ethoxy,propoxy, isopropoxy, or most advantageously methoxy.

Halogen (halo) preferably represents chloro or fluoro but may also bebromo or iodo.

Mono- or poly-halo-lower alkyl represents lower alkyl preferablysubstituted by one, two or three halogens, preferably fluoro or chloro,e.g. trifluoromethyl or trifluoroethyl.

Aryl represents carbocyclic or heterocyclic aryl.

Prodrug acyl derivatives are preferably those derived from an organiccarbonic acid, an organic carboxylic acid or a carbamic acid.

An acyl derivative which is derived from an organic carboxylic acid is,for example, lower alkanoyl, phenyl-lower alkanoyl or unsubstituted orsubstituted aroyl, such as benzoyl.

An acyl derivative which is derived from an organic carbonic acid is,for example, alkoxycarbonyl, especially lower alkoxycarbonyl, which isunsubstituted or substituted by carbocyclic or heterocyclic aryl or iscycloalkoxycarbonyl, especially C₃ -C₇ -cycloalkyloxycarbonyl, which isunsubstituted or substituted by lower alkyl.

An acyl derivative which is derived from a carbamic acid is, forexample, amino-carbonyl which is substituted by lower alkyl, carbocyclicor heterocyclic aryl-lower alkyl, carbocyclic or heterocyclic aryl,lower alkylene or lower alkylene interrupted by O or S.

Prodrug optionally substituted O-benzyl derivatives are preferablybenzyl or benzyl mono-, di-, or tri-substituted by e.g. lower alkyl,lower alkoxy, amino, nitro, halogen and/or trifluoromethyl.

Carbocyclic aryl represents monocyclic or bicyclic aryl, for examplephenyl or phenyl mono-, di- or tri-substituted by one, two or threeradicals selected from lower alkyl, lower alkoxy, hydroxy, halogen,cyano, trifluoromethyl, lower alkylenedioxy and oxy-C₂ -C₃ -alkylene; or1- or 2-naphthyl. Lower alkylenedioxy is a divalent substituent attachedto two adjacent carbon atoms of phenyl, e.g. methylenedioxy orethylenedioxy. Oxy-C₂ -C₃ -alkylene is also a divalent substituentattached to two adjacent carbon atoms of phenyl, e.g. oxyethylene oroxypropylene. An example for oxy-C₂ -C₃ -alkylene-phenyl is2,3-dihydrobenzofuran-5-yl.

Preferred as carbocyclic aryl is phenyl or phenyl monosubstituted bylower alkoxy, halogen, lower alkyl or trifluoromethyl, especially phenylor phenyl monosubstituted by lower alkoxy, halogen or trifluoroethyl,and in particular phenyl.

Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, forexample pyridyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl,benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, orany said radical substituted, especially mono- or di-substituted, bye.g. lower alkyl or halogen. Pyridyl represents 2-, 3- or 4-pyridyl,advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl,advantageously 2-thienyl. Quinolinyl represents preferably 2-, 3- or4-quinolinyl, advantageously 2-quinolinyl. Isoquinolinyl representspreferably 1-, 3- or 4-isoquinolinyl. Benzopyranyl, benzothiopyranylrepresent preferably 3-benzopyranyl or 3-benzothiopyranyl, respectively.Thiazolyl represents preferably 2- or 4-thiazolyl, advantageously4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(1,2,4-triazolyl).Tetrazolyl is preferably 5-tetrazolyl. Imidazolyl is preferably4-imidazolyl.

Preferably, heterocyclic aryl is pyridyI, quinolinyl, pyrrolyl,thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl,thienyl, or any said radical substituted, especially mono- ordi-substituted, by lower alkyl or halogen; and in particular pyridyl.

Biaryl is preferably carbocyclic biaryl, e.g. biphenyl, namely 2, 3 or4-biphenyl, advantageously 4-biphenyl, each optionally substituted bye.g. lower alkyl, lower alkoxy, halogen, trifluoromethyl or cyano.

C₃ -C₁₀ -Cycloalkyl represents a saturated cyclic hydrocarbon optionallysubstituted by lower alkyl which contains 3 to 10 ring carbons and isadvantageously cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyloptionally substituted by lower alkyl.

(Oxa or thia)-C₃ -C₆ -cycloalkyl represents a saturated cyclic radicalwherein 1 or 2, preferably 1, oxygen or sulfur atom(s) and preferably4-5 carbon atoms form a ring, e.g. tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothiopyranyl or tetrahydrothienyl.

Oxa-cyclohexane means tetahydropyran, and thia-cyclohexane meanstetrahydrothiopyran.

Carbocyclic aryl-lower alkyl represents preferably straight chain orbranched aryl-C₁ -C₄ -alkyl in which carbocyclic aryl has meaning asdefined above, e.g. benzyl or phenyl-(ethyl, propyl or butyl), eachunsubstituted or substituted on phenyl ting as defined under carbocyclicaryl above, advantageously optionally substituted benzyl.

Heterocyclic aryl-lower alkyl represents preferably straight chain orbranched heterocyclic aryl-C₁ -C₄ -alkyl in which heterocyclic aryl hasmeaning as defined above, e.g. 2-, 3- or 4-pyridylmethyl or (2-, 3- or4-pyridyl)-(ethyl, propyl or butyl); or 2- or 3-thienylmethyl or (2- or3-thienyl)-(ethyl, propyl or butyl); 2-, 3- or 4-quinolinylmethyl or(2-, 3- or 4-quinolinyl)-(ethyl, propyl or butyl); or 2- or4-thiazolylmethyl or (2-. or 4-thiazolyl)-(ethyl, propyl or butyl).

Cycloalkyl-lower alkyl represents e.g. (cyclopentyl- orcyclohexyl)-(methyl or ethyl).

Biaryl-lower alkyl represents e.g. 4-biphenylyl-(methyl or ethyl).

Acyl is derived from an organic carboxylic acid, carbonic acid orcarbamic acid.

Acyl represents e.g. lower alkanoyl, carbocyclic aryl-lower alkanoyl,lower alkoxycarbonyl, aroyl, di-lower alkylaminocarbonyl or di-loweralkylamino-lower alkanoyl. Preferably, acyl is lower alkanoyl.

Acylamino represents e.g. lower alkanoylamino or loweralkoxycarbonylamino.

Acylamino-lower alkyl in R and R₁ is R₃ -CONH-lower alkyl in which R₃represents e.g. lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-loweralkoxy, carbocyclic or heterocyclic aryl, di-lower alkylamino, N-loweralkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino,N-alkylpiperidyl, or (di-lower alkylamino, N-lower alkyl piperazino,morpholino, thiomorpholino, piperidino, pyrrolidino, pyridyl or N-loweralkyl-piperidyl)-lower alkyl.

Lower alkanoyl represents e.g. C₁ -C₇ -alkanoyl including formyl, and ispreferably C₂ -C₄ -alkanoyl such as acetyl or propionyl.

Aroyl represents e.g. benzoyl or benzoyl mono- or di-substituted by oneor two radicals selected from lower alkyl, lower alkoxy, halogen, cyanoand trifluoromethyl; or 1- or 2-naphthoyl; and also e.g.pyridylcarbonyl.

Lower alkoxycarbonyl represents preferably C₁ -C₄ -alkoxycarbonyl, e.g.ethoxycarbonyl.

Lower alkylene represents either straight chain or branched alkylene of1 to 7 carbon atoms and represents preferably straight chain alkylene of1 to 4 carbon atoms, e.g. a methylene, ethylene, propylene or butylenechain, or said methylene, ethylene, propylene or butylene chainmono-substituted by C₁ -C₃ -alkyl (advantageously methyl) ordisubstituted on the same or different carbon atoms by C₁ -C₃ -alkyl(advantageously methyl), the total number of carbon atoms being up toand including 7.

Esterified carboxyl is for example lower alkoxycarbonyl orbenzyloxycarbonyl.

Amidated carboxyl is for example aminocarbonyl, mono- or di-loweralkylaminocarbonyl.

Pharmaceutically acceptable salts of the acidic compounds of theinvention are salts formed with bases, namely cationic salts such asalkali and alkaline earth metal salts, such as sodium, lithium,potassium, calcium, magnesium, as well as ammonium salts, such asammonium, trimethyl-ammonium, diethylammonium, andtris-(hydroxymethyl)-methylammonium salts.

Similarly acid addition salts, such as of mineral acids, organiccarboxylic and organic sulfonic acids e.g. hydrochloric acid,methanesulfonic acid, maleic acid, are also possible provided a basicgroup, such as pyridyl, constitutes part of the structure.

The compounds of the invention exhibit valuable pharmacologicalproperties in mammals including man and are particularly useful asinhibitors of matrix-degrading metalloproteinase enzymes(=metalloproteinases).

As the compounds of the invention are inhibitors of stromelysin,gelatinase, collagenase and macrophage metalloelastase, and inhibitmatrix degradation, they are particularly useful in mammals as agentsfor the treatment of e.g. osteoarthritis, rheumatoid arthritis, cornealulceration, periodontal disease, tumor metastasis, tumor invasion orprogression, progression of HIV-infection and HIV-infection relateddisorders, atherosclerosis, osteoporosis and emphysema.

Illustrative of the matrix degrading metalloproteinase inhibitoryactivity, compounds of the invention prevent the degradation ofcartilage caused by exogenous or endogenous stromelysin in mammals. Theyinhibit e.g. the stromelysin-induced degradation of aggrecan (largeaggregating proteoglycan), link protein or type IX collagen in mammals.

Beneficial effects are evaluated in pharmacological tests generallyknown in the art, and as illustrated herein.

The above-cited properties are demonstrable in in vitro and in vivotests, using advantageously mammals, e.g. rats, guinea pigs, dogs,rabbits, or isolated organs and tissues, as well as mammalian enzymepreparations. Said compounds can be applied in vitro in the form ofsolutions, e.g. preferably aqueous solutions, and in vivo eitherenterally or parenterally, advantageously orally, e.g. as a suspensionor in aqueous solution. The dosage in vitro may range between about 10⁻⁵molar and 10⁻¹⁰ molar concentrations. The dosage in vivo may range,depending on the route of administration, between about 0.1 and 50mg/kg.

One test to determine the inhibition of stromelysin activity is based onits hydrolysis of Substance P using a modified procedure of Harrison etal (Harrison, R. A., Teahan J., and Stein R., A semicontinuous, highperformance chromatography based assay for stromelysin, Anal. Biochem.180, 110-113 (1989)). In this assay, Substance P is hydrolyzed byrecombinant human stromelysin to generate a fragment, Substance P 7-11,which can be quantitated by HPLC. In a typical assay, a 10 mM stocksolution of a compound to be tested is diluted in the assay buffer to 50μM, mixed 1:1 with 8 μg recombinant human stromelysin (mol. wt. 45-47kDa, 2 Units; where 1 Unit produces 20 mmoles of Substance P 7-11 in 30minutes) and incubated along with 0.5 mM Substance P in a final volumeof 0.125 ml for 30 minutes at 37° C. The reaction is stopped by adding10 mM EDTA and Substance P 7-11 is quantified on RP-8 HPLC. The IC₅₀ forinhibition of stromelysin activity and Ki are calculated from controlreaction without the inhibitor.

Illustrative of the invention,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride exhibits a Ki of 17 nM in this assay.

Stromelysin activity can also be determined using human aggrecan as asubstrate. This assay allows the confirmation in-vitro that a compoundcan inhibit the action of stromelysin on its highly negatively-chargednatural substrate, aggrecan (large aggregating proteoglycan). Within thecartilage, proteoglycan exists as an aggregate bound to hyaluronate.Human proteoglycan aggregated to hyaluronate is used as an enzymesubstrate. The assay is set up in 96-well microtiter plates allowingrapid evaluation of compounds. The assay has three major steps:

1) Plates are coated with hyaluronate (human umbilical chord, 400ug/ml), blocked with BSA (5 mg/ml), and then proteoglycan (humanarticular cartilage D1 - chondroitinase ABC digested, 2 mg/ml) is boundto the hyaluronate. Plates are washed between each step.

2) Buffers+inhibitor (1 to 5,000 nM)+recombinant human stromelysin (1-3Units/well) are added to wells. The plates are sealed with tape andincubated overnight at 37° C. The plates are then washed.

3) A primary (3B3) antibody (mouse IgM, 1:10,000) is used to detectremaining fragments. A secondary antibody, peroxididase-linked anti-IgM,is bound to the primary antibody. OPD is then added as a substrate forthe peroxidase and the reaction is stopped with sulfuric acid. The IC₅₀for inhibition of stromelysin activity is graphically derived and Ki iscalculated.

Illustrative of the invention,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride exhibits an IC₅₀ of 55 nM in this assay.

Collagenase activity is determined as follows: ninety six-well,fiat-bottom microtiter plates are first coated with bovine type Icollagen (35 ug/well) over a two-day period at 30° C. using a humidifiedand then dry atmosphere; plates are rinsed, air dried for 3-4 hours,sealed with Saran wrap and stored in a refrigerator. Human recombinantfibroblast collagenase and a test compound (or buffer) are added towells (total volume=0.1 ml) and plates are incubated for 2 hours at 35°C. under humidified conditions; the amount of collagenase used per wellis that causing approximately 80% of maximal digestion of collagen. Theincubation media are removed from the wells, which are then rinsed withbuffer, followed by water. Coomasie blue stain is added to the wells for25 minutes, removed, and wells are again rinsed with water. Sodiumdodecyl sulfate (20% in 50% dimethylformamide in water) is added tosolubilize the remaining stained collagen and the optical density at 570nM wave length is measured. The decrease in optical density due tocollagenase (from that of collagen without enzyme) is compared to thedecrease in optical density due to the enzyme in the presence of testcompound, and percent inhibition of enzyme activity is calculated. IC₅₀'s are determined from a range of concentrations of inhibitors (4-5concentrations, each tested in triplicate), and K_(i) values arecalculated.

Illustrative of the invention,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride exhibits a Ki of 62 nM in this assay.

The effect of compounds of the invention in-vivo can be determined inrabbits. Typically, four rabbits are dosed orally with a compound up tofour hours before being injected intra-articularly in both knees (N=8)with 40 Units of recombinant human stromelysin dissolved in 20 mM Tris,10 mM CaCl₂, and 0.15 M NaCl at pH 7.5. Two hours later the rabbits aresacrificed, synovial lavage is collected, and keratan sulfate (KS) andsulfated glycosaminoglycan (S-GAG) fragments released into the joint arequantitated. Keratan sulfate is measured by an inhibition ELISA usingthe method of Thonar (Thonar, E. J.-M. A., Lenz, M. E., Klinsworth, G.K., Caterson, B., Pachman, L. M., Clickman, P.., Katz, R., Huff, J.,Keuttner, K. E. Quantitation of keratan sulfate in blood as a marker ofcartilage catabolism, Arthr. Rheum. 28, 1367-1376 (1985)). Sulfatedglycosaminoglycans are measured by first digesting the synovial lavagewith streptomyces hyaluronidase and then measuring DMB dye binding usingthe method of Goldberg (Goldberg, R. L. and Kolibas, L. An improvedmethod for determining proteoglycan synthesized by chondrocytes inculture. Connect. Tiss. Res. 24,, 265-275 (1990)). For an i.v. study, acompound is solubilized in 1 ml of PEG-400, and for a p.o. study, acompound is administered in 5 ml of fortified corn starch per kilogramof body weight.

Illustrative of the invention,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride produces a 72% and 70% inhibition, respectively, in therelease of KS and S-GAG fragments into the joint when given to rabbitsat a dose of 30 mg/kg, 4 hours prior to the injection of humanrecombinant stromelysin.

The effect in protecting against cartilage degradation in arthriticdisorders can be determined e.g. in a surgical model of osteoarthritisdescribed in Arthritis and Rheumatism, Vol. 26, 875-886 (1983).

Illustrative of the invention,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride protects against cartilage degradation in this model.

The effect on ulcerations, e.g. ocular ulcerations, can be determined inthe rabbit by measuring the reduction of corneal ulceration following analkali burn to the cornea.

Macrophage metalloelastase (MME) inhibitory activity can be determinedby measuring the inhibition of the degradation of [³ H]-elastin bytruncated recombinant mouse macrophage metalloelastase as follows:

About 2 ng of recombinant truncated mouse macrophage metalloelastase(FASEB Journal Vol. 8, A151, 1994), purified by Q-Sepharose columnchromatography is incubated with test compounds at the desiredconcentrations in the presence of 5 nM CaCl₂, 400 nM NAC;, [³ H]elastin(60,000 cpm/tube), and 20 mM Tris, pH 8.0, at 37° C. overnight. Thesamples are spun in a microfuge centrifuge at 12,000 rpm for 15 minutes.An aliquot of the supernatant is counted in a scintillation counter toquantitate degraded [³ H]elastin. IC₅₀ 's are determined from a range ofconcentrations of the test compounds and the percent inhibition ofenzyme activity obtained.

Illustrative of the invention,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride inhibits the degradation of [³ H] elastin by mousemacrophage metalloelastase with an IC₅₀ of about 8nM.

The effect of the compounds of the invention for the treatment ofemphysema can be determined in animal models described in AmericanReview of Respiratory Disease 117, 1109 (1978).

Inhibition of the production and secretion of TNF-α can be determinede.g. as described in Nature 370, 555, 558 (1994). Anti-inflammatoryactivity can be determined in standard inflammation and arthritic animalmodels well-known in the art, e.g. the adjuvant arthritis model in rats.

The compounds of formula I can be prepared e.g. by condensing acarboxylic acid of formula IV, ##STR8## or a reactive functionalderivative thereof, wherein R, R₁, R₂ and Ar having meaning as definedin claim 1, with hydroxylamine of formula V,

    NH.sub.2--OH                                               (V)

optionally in protected form, or a salt thereof;

and, if necessary, temporarily protecting any interfering reactivegroup(s), and then liberating the resulting compound of the invention;and, if required or desired, convening a resulting compound of theinvention into another compound of the invention, and/or, if desired,convening a resulting free compound into a salt or a resulting salt intoa free compound or into another salt; and/or separating a mixture ofisomers or racemates obtained into the single isomers or racemates;and/or, if desired, resolving a racemate into the optical antipodes.

In starting compounds and intermediates which are convened to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, carboxyl and hydroxygroups are those that can be convened under mild conditions into freeamino and hydroxy groups without the molecular framework being destroyedor other undesired side reactions taking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxy group, aminogroup, etc.), the structure and stability of the molecule of which thesubstituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in J. F. W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London, N.Y.,1973, T. W. Greene, "Protective Groups in Organic Synthesis", Wiley,N.Y., 1991.

In the processes cited herein, reactive functional derivatives ofcarboxylic acids represent, for example, anhydrides especially mixedanhydrides, acid halides, acid azides, lower alkyl esters and activatedesters thereof. Mixed anhydrides are preferably such from pivalic acid,or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acidhalides are for example chlorides or bromides; activated esters forexample succinimido, phthalimido or 4-nitrophenyl esters; lower alkylesters am for example the methyl or ethyl esters.

Also, a reactive esterified derivative of an alcohol in any of thereactions cited herein represents said alcohol esterified by a strongacid, especially a strong inorganic acid, such as a hydrohalic acid,especially hydrochloric, hydrobromic or hydroiodic acid, or sulphuricacid, or by a strong organic acid, especially a strong organic sulfonicacid, such as an aliphatic or aromatic sulfonic acid, for examplemethanesulfonic acid, 4-methylbenzenesulfonic acid or4-bromobenzenesulfonic acid. A said reactive esterified derivative isespecially halo, for example chloro, bromo or iodo, or aliphatically oraromatically substituted sulfonyloxy, for example methanesulfonyloxy,4-methylbenzenesulfonyloxy (tosyloxy).

In the above processes for the synthesis of compounds of the inventioncan be carried out according to methodology generally known in the artfor the preparation of hydroxamic acids and derivatives thereof.

The synthesis according to the above process (involving the condensationof a free carboxylic acid of formula IV with an optionally hydroxyprotected hydroxylamine derivative of formula V can be carried out inthe presence of a condensing agent, e.g. 1,1'-carbonyldiimidazole, orN-(dimethylaminopropyl)-N'-ethylcarbodiimide ordicyclohexylcarbodiimide, with or without 1-hydroxybenzotriazole in aninert polar solvent, such as dimethylformamide or dichloromethane,preferably at room temperature.

The synthesis involving the condensation of a reactive functionalderivative of an acid of formula IV as defined above, e.g. an acidchloride or mixed anhydride with optionally hydroxy protectedhydroxylamine, or a salt thereof, in presence of a base such astriethylamine can be carried out, at a temperature ranging preferablyfrom about -78° C. to +75° C., in an inert organic solvent such asdichloromethane or toluene..

Protected forms of hydroxylamine (of formula V) in the above process arethose wherein the hydroxy group is protected for example as a t-butylether, a benzyl ether or tetrahydropyranyl ether, or as a trimethylsilylderivative. Removal of said protecting groups is carried out accordingto methods well known in the art, e.g. hydrogenolysis or acidhydrolysis. Hydroxylamine is preferably generated in sire from ahydroxylamine salt, such as hydroxylamine hydrochloride.

The starting carboxylic acids of formula IV can be prepared as follows:

An amino acid of formula VI ##STR9## wherein R₁ and R₂ have meaning asdefined herein, is first esterified with a lower alkanol, e.g. methanol,in the presence of e.g. thionyl chloride to obtain an aminoester whichis treated with a reactive functional derivative of the appropriatearylsulfonic acid of the formula VII

    ArSO.sub.3 H                                               (VII)

wherein Ar has meaning as defined hereinabove, e.g. with thearylsulfonyl chloride, in the presence of a suitable base such astriethylamine using a polar solvent such as tetrahydrofuran, toluene,acetonitrile to obtain a compound of the formula VIII ##STR10## whereinR₁, R₂ and Ar have meaning as defined herein and R₆ is a protectinggroup, e.g. lower alkyl. Treatment thereof with a reactive esterifiedderivative of the alcohol of the formula IX

    R--CH.sub.2 OH                                             (IX)

wherein R has meaning as defined herein, such as the halide, e.g. thechloride, bromide or iodide derivative thereof, in the presence of anappropriate base, such as potassium carbonate or sodium hydride, in apolar solvent such as dimethylformamide. The resulting compoundcorresponding to an ester of a compound of formula IV can then behydrolyzed to the acid of formula IV, using standard mild methods ofester hydrolysis, preferably under acidic conditions. For compounds offormula Ia (wherein R and R₁ of formula I are combined) the startingmaterials are prepared by treating a carboxylic acid of formula X##STR11## or an ester thereof, wherein R₂ and X have meaning as definedabove, with a reactive functional derivative of a compound of theformula ArSO₃ H (VII) under conditions described for the preparation ofa compound of formula VIII.

The starting materials of formula VI, VII, IX and X are either known inthe art, or can be prepared by methods well-known in the art or asdescribed herein.

Optically active D-aminoacids of formula VI (the R-enantiomers) can beprepared according to methods known in the art, e.g. according tomethods described in Tetrahedron Letters 28, 39 (1987), J. Am. Chem.Soc. 109, 7151 (1987) and J. Am. Chem. Soc. 110, 1547 (1988).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures (preferably ator near the boiling point of the solvents used), and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carded out, or the processis discontinued at any stage thereof, or i, which the starting materialsare formed in situ under the reaction conditions, or in which thereaction components are used in the form of their salts or opticallypure antipodes.

Compounds of the invention and intermediates can also be convened intoeach other according to methods generally known per se.

The invention also relates to any novel starting materials and processesfor their manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, optical isomers (antipodes), racemates, or mixtures thereof.The aforesaid possible isomers or mixtures thereof are within thepurview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysico-chemical differences of the constituents, into the puregeometric or optical isomers, diastereoisomers, racemates, for exampleby chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g. by separationof the diastereoisomeric salts thereof, obtained with an opticallyactive acid or base, and liberating the optically active acidic or basiccompound. The hydroxamic acids or carboxylic acid intermediates can thusbe resolved into their optical antipodes e.g. by fractionalcrystallization of d- or 1-(alpha-methylbenzylamine, cinchonidine,cinchonine, quinine, quinidine, ephedrine, dehydro-abietylamine, brucineor strychnine)-salts.

Finally, acidic compounds of the invention are either obtained in thefree form, or as a salt thereof.

Acidic compounds of the invention may be convened into salts withpharmaceutically acceptable bases, e.g. an aqueous alkali metalhydroxide, advantageously in the presence of an ethereal or alcoholicsolvent, such as a lower alkanol. From the solutions of the latter, thesalts may be precipitated with ethers, e.g. diethyl ether. Resultingsalts may be convened into the free compounds by treatment with acids.These or other salts can also be used for purification of the compoundsobtained.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, to inhibit matrix-degradingmetalloproteinases, and for the treatment of disorders responsivethereto, comprising an effective amount of a pharmacologically activecompound of the invention, alone or in combination, with one or morepharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectivemount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. Preferred aretablets and gelatin capsules comprising the active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol; fortablets also c) binders e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose andor polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, or effervescent mixtures; and/ore) absorbants, colorants, flavors and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Said compositions are prepared according toconventional mixing, granulating or coating methods, respectively, andcontain about 0.1 to 75%, preferably about 1 to 50%, of the activeingredient.

Suitable formulations for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. Characteristically,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound of theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin.

Suitable formulations for topical application, e.g. to the skin andeyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art.

The pharmaceutical formulations contain an effective matrix-degradingmetalloproteinase inhibiting amount of a compound of the invention asdefined above either alone, or in combination with another therapeuticagent, e.g. an anti-inflammatory agent with cyclooxygenase inhibitingactivity, each at an effective therapeutic dose as reported in the art.Such therapeutic agents are well-known in the art.

Examples of antiinflammatory agents with cyclooxygenase inhibitingactivity are diclofenac sodium, naproxen, ibuprofen, and the like.

In conjunction with another active ingredient, a compound of theinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration. A unit dosage for oraladministration to a mammal of about 50 to 70 kg may contain betweenabout 25 and 250 mg of the active ingredient.

The present invention also relates to methods of using the compounds ofthe invention and their pharmaceutically acceptable salts, orpharmaceutical compositions thereof, in mammals for inhibiting thematrix-degrading metalloproteinases, e.g. stromelysin, collagenase andmacrophage metalloelastase, for inhibiting tissue matrix degradation,and for the treatment of matrix-degrading metalloproteinase dependentconditions as describe41 herein, e.g. osteoarthritis, also tumormetastasis, progression or invasion, pulmonary disorders, and the likedescribed herein.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg (=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR).Abbreviations used are those conventional in the art. The concentrationfor [α]_(D) determinations is expressed in mg/ml.

EXAMPLE 1

(a)N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide(4.1 g, 9.13 mmol) is dissolved in dichloroethane (150 mL) containingethanol (0.53ml, 9.13 mmol) in a round bottom flask, and the reaction iscooled to -10° C. Hydrochloric acid gas (from a lecture bottle) isbubbled through for 30 minutes. The reaction is sealed, allowed toslowly warm to room temperature, and stirred for 2 days. The solvent isreduced to 1/3 volume by evaporation and triturated with ether. Themixture is filtered, falter cake removed, and dried in vacuo to provideN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride as a white solid, m.p. 169°-170° C. (dec), and having thefollowing structure: ##STR12##

The starting material is prepared as follows:

To a solution of D-valine (15.0 g, 128.0 mmol) in 1:1 dioxane/water (200mL) containing triethylamine (19.4 g, 192.0 mmol) at room temperature isadded 4-methoxybenzenesulfonyl chloride (29.0 g, 141.0 mmol), and thereaction mixture is stirred at room temperature overnight. The mixtureis then diluted with methylene chloride, washed with 1N aqueoushydrochloric acid and water. The organic layer is washed again withbrine, dried (Na₂ SO₄), and the solvent is evaporated to provideN-[4-methoxybenzenesulfonyl]-(D)-valine as a crude product. A :solutionof this crude product (15.0 g) in toluene (100 mL) containingN,N-dimethylformamide di-t-butyl acetal (50 mL, 206.5 mmol) is heated to95° C. for 3 hours. The solvent is then evaporated. The crude product ispurified by silica gel chromatography (30% ethyl acetate/hexanes) toprovide N-[4-methoxybenzenesulfonyl]-(D)-valine t-butyl ester.

To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine t-butyl ester(4.38 g, 13.0 mmol) in dimethylformamide (200 mL) is added 3-picolylchloride hydrochloride (2.3 g, 14.0 mmol) followed by potassiumcarbonate (17.94 g, 130.0 mmol). The reaction mixture is stirred at roomtemperature for 2 days. The mixture is then diluted with water andextracted with ethyl acetate. The combined organic extracts are washedwith brine, dried (Na₂ SO₄), and the solvent is evaporated. The crudeproduct is purified by silica gel chromatography (ethyl acetate) to givet-butyl2(R)-[N-[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanoate.

t-Butyl2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoate (5.3g, 12.2 mmol) is dissolved in methylene chloride (150 mL) and cooled to-10° C. Hydrochloric acid gas is bubbled into the solution for 10minutes. The reaction mixture is then sealed, warmed to room temperatureand stirred for 4 hours. The solvent is then evaporated to provide2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acidhydrochloride.

2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acidhydrochloride (5.0 g, 12.06 mmol), 1-hydroxybenzotriazole (1.63 g, 12.06mmol), 4-methylmorpholine (6.6 mL, 60.31 mmol), andO-t-butylhydroxylamine hydrochloride (54.55 g, 36.19 mmol) are dissolvedin methylene chloride (200 mL).N-[Dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.01 g,15.68 mmol) is added, and the reaction is stirred overnight. Thereaction is then diluted with water and extracted with methylenechloride. The combined organic extracts are washed with brine, dried(Na₂ SO₄), and the solvent is evaporated. The crude product is purifiedby silica gel chromatography (2% methanol/methylene chloride) to giveN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide.

(b) L-tartaric acid salt, m.p. 114°-116° C.

(c) Methanesulfonic acid salt, m.p. 139°-141.5° C.

(d) Maleic acid salt, m.p. 133°-134° C.

EXAMPLE 2

The following compounds are prepared similarly to Example 1:

a)N-Hydroxy-2(S)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamidehydrochloride, m.p. 170.5°-171° C., by starting the synthesis withL-valine, and carrying out the subsequent steps as described above.

(b)N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-4-methylpentanamidehydrochloride, m.p. 128°-129° C.

The first two steps are carried out as described in example 1, exceptthe synthesis was started with D-leucine. The alkylation step isdifferent, as described below.

To a solution of t-butyl2(R)-[[4-methoxybenzenesulfonyl]amino]4-methylpentanoate (10.0 g, 27.92mmol) in dimethylformamide (250 mL) at room temperature is added3-picolyl chloride hydrochloride (4.81 g, 29.32 mmol) followed by sodiumhydride (2.79 g, 69.80 mmol, 60% in oil). The reaction mixture isstirred at room temperature for 48 hours. The mixture is quenched withwater and extracted with ethyl acetate. The combined organic extractsare washed with brine, dried (Na₂ SO₄), and the solvent is evaporated.The crude product is purified by silica gel chromatography (45% ethylacetate/hexanes) to provide t-butyl2CR)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-4-methylpentanoate.

All of the following steps are carried out as described above in example1.

(c)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](6-chloropiperonyl)amino]-4-methylpentanamide,m.p. 85°-87° C., by starting the synthesis with D-leucine and alkylatingwith 6-chloropiperonyl chloride(=6-chloro-3,4-methylenedioxy-benzylchloride) in the third step.

(d)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](piperonyl)amino]-4-methylpentanamide,m.p. 145°-147° C., by starting the synthesis with D-leucine andalkylating with piperonyl chloride (=3,4-methylenedioxy-benzylchloride)in the third step.

(e)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](2-picolyl)amino]-4-methylpentanamide,m.p. 89°-90° C., by starting the synthesis with D-leucine and alkylatingwith 2-picolyl chloride in the third step.

(f)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](2-picolyl)amino]-3-methylbutanamidehydrochloride, m.p. 140°-142° C., by starting the synthesis withD-valine and alkylating with 2-picolyl chloride in the third step.

(g)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-4,4-dimethylpentanamide hydrochloride, m.p. 130°-150° C. (slow melt), by starting thesynthesis with D-t-butylalanine and alkylating with 3-picolyl chloridein the third step.

(h)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-cyclohexylacetamidehydrochloride, m.p. 149°-152.0° C., by starting the synthesis with(D)-cyclohexylglycine hydrochloride.

The starting amino acid is prepared as follows:

(D)-phenylglycine (10.0 g, 66.2 mmol) is suspended in 2N hydrochloricacid (100 mL) containing platinum (IV) oxide hydrate (267 mg). Themixture is shaken in a Parr hydrogenation apparatus for 24 hours under ahydrogen pressure of 50 psi. The resultant suspended crystallinematerial, (D)-cyclohexylglycine hydrochloride, was used without furtherpurification.

(i)N-Hydroxy-2(R)-[[(2,3-dihydrobenzofuran)-5-sulfonyl](3-picolyl)amino]3-methylbutanamidehydrochloride, m.p. 150.0°-153.0° C., by starting the synthesis with2,3-dihydrobenzofuran-5-sulfonyl chloride.

The starting sulfonyl chloride is prepared as follows:

2,3-dihydrobenzofuran (6.0 g, 49.94 mmol) is added over 20 minutes tochlorosulfonic acid (29.09 g, 249.69 mmol) at -20° C. The reactionmixture is quenched by addition of ice followed by water (20 mL). Themixture is then extracted with ethyl acetate. The combined organicestracts are washed with brine, dried (Na₂ SO₄), and the solvent isevaporated. The crude product is purified by silica gel chromatography(30% ethyl acetate/hexane) to give 2,3-dihydrobenzofuran-5-sulfonylchloride (3.3 g).

(j) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-3-methylbutanamide hydrochloride, m.p. 139.5°-142° C., by starting thesynthesis with DL-valine.

(k)N-Hydroxy-2(R)-[[4-ethoxybenzenesulfonyl](3-picolyl)-amino]-3-methylbutanamidehydrochloride, [α]_(D) ²⁵ =-34.35 (c=5.84, CH₃ OH).

(1)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](2-picolyl)amino]-2-cyclohexylacetamidehydrochloride, m.p. 127°-140°, by starting the syntheses with(D)-cyclohexylglycine hydrochloride, and carrying out the subsequentsteps as described above.

(m)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-methylthiazol-4-ylmethyl)amino]-2-cyclohexylacetamidehydrochloride, m.p. 137°-139° C., using 4-chloromethyl-2-methylthiazolein the alkylation step.

(n)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]-2-cyclohexylacetamidehydrochloride, m.p. 121°-123° C., using 2-chloromethylquinolinehydrochloride in the alkylation step.

EXAMPLE 3

2(R)-[[4-Methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoic acid(4.38 g, 11.2 mmol) is dissolved in methylene chloride (56.0 mL). Tothis solution is added oxalyl chloride (1.95 mL, 22.4 mmol) anddimethylformamide (0.86 mL, 11.2 mmol), and the reaction is stirred atroom temperature for 90 minutes. Meanwhile, in a separate flask,hydroxylamine hydrochloride (3.11 g, 44.8 mmol) and triethylamine (9.36mL, 67.1 mmol) are stirred in tetrahydrofuran (50.0 mL) and water (3.5mL) at 0° C. for 15 minutes. After 90 minutes, the methylene chloridesolution is added in one portion to the second flask, and the combinedcontents are stirred for three days as the flask gradually warms up toroom temperature. The reaction is then diluted with acidic water(pH=˜3), and extracted several times with ethyl acetate. The combinedorganic layers are dried (Na₂ SO₄), and the solvent is evaporated. Theproduct is purified by silica gel chromatography (1% methanol/methylenechloride) to giveN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanamide,m.p. 48°-52° C.

The starting material is prepared as follows:

(D)-leucine (7.1 g, 53.9 mmol) is dissolved in dioxane (60.0 mL) andwater (60.0 mL). To this solution is added triethylamine (11.3 mL, 80.9mmol) and 4-methoxybenzenesulfony chloride 02.25 g, 59.3 mmol), and thereaction is stirred at room temperature overnight. The reaction is thendiluted with methylene chloride and washed successively with 2.5Nhydrochloric acid, water, and brine. The organic phase is dried (Na₂SO₄), and the solvent is evaporated to giveN-[4-methoxybenzenesulfonyl]-(D)-leucine, which is used without furtherpurification.

N-[4-methoxybenzenesulfonyl]-(D)-leucine (14.0 g, 46.5 mmol) isdissolved in toluene (100.0 mL), and heated to 90° C.N,N-Dimethylformamide di-t-butyl acetal (45.0 mL, 186.0 mmol) is addeddropwise over 20 minutes, and then the reaction is kept at 90° C. foranother 2 hours. After cooling back down, the reaction is diluted withethyl acetate and washed successively with saturated sodium bicarbonate,water, and brine. The organic phase is dried (Na₂ SO₄), and the solventis evaporated. The product is purified by silica gel chromatography (20%ethyl acetate/hexane) to give N-[4-methoxybenzenesulfonyl]-(D)-leucinet-butyl ester.

To a suspension of sodium hydride (0.68 g, 14.1 mmol) indimethylformamide (60.0 mL), is addedN-[4-methoxybenzenesulfonyl]-(D)-leucine t-butyl ester (5.02 g, 14.06mmol) in dimethylformamide (10.0 mL). After stirring at room temperaturefor 20 minutes, benzyl bromide (1.67 mL, 14.06 mmol) is added, and thereaction is stirred overnight at room temperature. The reaction is thenpartitioned between ethyl acetate and acidic water (pH=5), the organiclayer is dried (Na₂ SO₄), and the solvent is evaporated. The product ispurified by silica gel chromatography (10% ethyl acetate/hexane) to givet-butyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoate.

t-Butyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoate (5.38 g, 12.02 mmol) is dissolved in methylene chloride (100.0 mL).Hydrochloric acid gas (from a lecture bottle) is bubbled through thesolution for 20 minutes. The reaction is sealed and stirred overnight atroom temperature, The solvent is then evaporated to give2(R)-[[4methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoic acid.

EXAMPLE 4

The following compounds are prepared similarly to example 3:

(a)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-phenylacetamide,m.p. 128°-129° C., by starting the synthesis with (D)-phenylglycine, andcarrying out the subsequent steps as described in example 3.

(b)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-t-butylacetamide,m.p. 69°-73° C., by starting the synthesis with t-butylglycine, andcarrying out the subsequent steps as described in example 3.

(c)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](4-fluorobenzyl)amino]-4-methylpentanamide,m.p. 48°-51° C., by starting the synthesis with (D)-leucine, andcarrying out the subsequent steps as described in example 3, with theexception that 4-fluorobenzyl bromide is used in place of benzylbromide.

(d)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-3-methylbutanamide,m.p. 179°-180° C., by starting the synthesis with (D)-valine, andcarrying out the subsequent steps as described in example 3.

(e)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4,4-dimethylpentanamide,by starting the synthesis with (D)-neopentylglycine, and carrying outthe subsequent steps as described in example 3.

(f)N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl(benzyl)amino]-3-hydroxypropanamide, m.p. 65°, by starting the synthesis with (D)-serine,and carrying out the subsequent steps as described in example 3.

EXAMPLE 5

3-[4-Methoxybenzenesulfonyl]-5,5-dimethylthiazolidine-4(S)-carboxylicacid (2.0 g, 6.0 mmol) is dissolved in methylene chloride (30.0 mL). Tothis solution is added oxalyl chloride (1.1 mL, 12.1 mmol) anddimethylformamide (0.50 mL, 6.0 mmol), and the reaction is stirred atroom temperature for 2 hours. Meanwhile, in a separate flask,hydroxylamine hydrochloride (1.74 g, 25.0 mmol) and triethylamine (5.0mL, 36.0 mmol) are stirred in tetrahydrofuran (25.0 mL) and water (2.0mL) at 0° C. for 15 minutes. After 2 hours, the methylene chloridesolution is added in one portion to the second flask, and the combinedcontents are stirred overnight as the flask gradually warms up to roomtemperature. The reaction is then diluted with acidic water (pH=˜3), andextracted several times with ethyl acetate. The combined organic layersare dried (Na₂ SO₄), and the solvent is evaporated. The product ispurified by silica gel chromatography (60% ethyl acetate/hexane) to giveN-hydroxy-3-[4-methoxybenzenesulfonyl]-5,5-dimethylthiazolidine-4(S)-carboxamide,m.p. 68°-71° C.

The starting material is prepared as follows:

(D)-5,5-Dimethylthiazolidine-4-carboxylic acid (1.0 g, 6.2 mmol) isdissolved in dioxane (10.0 mL) and water (10.0 mL). To this solution isadded triethylamine (1.3 mL, 9.3 mmol) and 4-methoxybenzenesulfonylchloride (1.41 g, 6.82 mmol), and the reaction is stirred at roomtemperature for three days. The reaction is then diluted with ethylacetate and washed successively with 2.5N hydrochloric acid, water, andbrine. The organic phase is dried (Na₂ SO₄), and the solvent isevaporated to give3-[4-methoxybenzenesulfonyl]-5,5-dimethylthiazolidine-4(S)-carboxylicacid, which is used without further purification.

EXAMPLE 6

1-[4-Methoxybenzenesulfonyl]-pyrrolidine-2(R)-carboxylic acid (1.12 g,3.93 mmol) is dissolved in methylene chloride (40.0 mL). To thissolution is added oxalyl chloride (0.69 mL, 7.85 mmol) anddimethylformamide (0.30 mL, 3.93 mmol), and the reaction is stirred atroom temperature for 30 minutes. Meanwhile, in a separate flask,hydroxylamine hydrochloride (1.1 g, 15.7 mmol) and triethylamine (3.3mL, 23.5 mmol) are stirred in tetrahydrofuran (20.0 mL) and water (4.0mL) at 0° C. for 15 minutes. After 30 minutes, the methylene chloridesolution is added in one portion to the second flask, and the combinedcontents are stirred overnight as the flask gradually warms up to roomtemperature. The reaction is then diluted with acidic water (pH=˜3), andextracted several times with ethyl acetate. The combined organic layersare dried (MgSO₄), and the solvent is evaporated. The product ispurified by silica gel chromatography (50% ethyl acetate/hexane) to giveN-hydroxy-1-[4-methoxybenzenesulfonyl]-pyrrolidine-2(S)-carboxamide,m.p. 163.5°-165.5° C.

The starting material is prepared as follows:

(D)-proline (0.78 g, 6.77 mmol) is suspended in methylene chloride (25.0mL). To this solution is added triethylamine (1.13 mL, 8.12 mmol) and4-methoxybenzenesulfonyl chloride (1.4 g, 6.77 mmol), and the reactionis stirred at room temperature for two days. The reaction is thendiluted with methylene chloride and washed successively with 1Nhydrochloric acid, water, and brine. The organic phase is dried (MgSO₄),and the solvent is evaporated. The product is purified by silica gelchromatography (10% methanol/ethyl acetate) to give1-[4-methoxybenzenesulfonyl]-pyrrolidine-2(R)-carboxylic acid.

EXAMPLE 7

N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]acetamide(2.65 g, 5.1 mmol) is dissolved in methylene chloride (30.0 mL) andethanol (1.0 mL) in a glass sealed tube, and the reaction is cooled to0° C. Hydrochloric acid gas (from a lecture bottle) is bubbled throughthe solution for 20 minutes, and then the tube is sealed and kept atroom temperature for 3 days. After that time, the solvent is removed,and the reaction is partitioned between ethyl acetate and saturatedsodium bicarbonate. The organic phase is dried (Na₂ SO₄), and thesolvent is evaporated. The product is purified by silica gelchromatography (2% methanol/methylene chloride) to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]acetamide,m.p. 56°-60° C.

The starting material is prepared as follows:

N-(2-chloroethyl)morpholine hydrochloride (1.2.0 g) is dissolved inwater (200 mL) and made basic with ammonium hydroxide (100.0 mL) to apH=˜1. The aqueous layer is then extracted several times with ether, thecombined organic layers are dried (Na₂ SO₄), and the solvent isevaporated to yield an oil which is used immediately.

Diethyl acetamidomalonate (11.4 g, 57.08 mmol) is added to a freshlyprepared solution of sodium ethoxide in ethanol (made from Na (1.32 g,57.1 mmol) added to ethanol (34.0 mL)), and the reaction is refluxed for30 minutes. The reaction is then adjusted to 55° C., and potassiumiodide (0.14 g, 0.8 mmol) and dimethylformamide (0.2 mL) are added.Finally, the N-(2-chloroethyl)morpholine (8.9 g, 59.6 mmol) preparedabove is added in ethanol (14.0 mL), and the reaction is maintained at55° C. for 24 hours.

The reaction is diluted with ethyl acetate and filtered through Celiteto remove salts. The filtrate is evaporated, and then partitionedbetween ethyl acetate and brine. The organic layer is dried (Na₂ SO₄),and the solvent is evaporated. The product is purified by silica gelchromatography (first 50% ethyl/acetate, then 5% methanol/methylenechloride) to give diethyl [2-(4-morpholino)ethyl]acetamidomalonate.

Diethyl [2-(4-morpholino)ethyl]acetamidomalonate (8.0 g, 25.6 mmol) isdissolved in ethanol (128.0 mL). Sodium hydroxide (4.55 mL of a 6Naqueous solution, 27.35 mmol) is added, and the reaction is stirred atroom temperature for 24 hours. The ethanol is then evaporated, and theresidue is diluted up in water, washed several times with ether, andthen the aqueous phase is acidified with concentrated hydrochloric acidto pH=˜5. The solution is evaporated to dryness, then suspended intoluene (300.0 mL) and refluxed for 3 hours. After cooling to roomtemperature, the reaction is diluted with chloroform (300.0 mL), and themixture is filtered through Celite. The filtrate is evaporated to giveethyl 2-(acetamido )-2-[2-(4-morpholino )ethyl]acetate.

Ethyl 2-(acetamido)-2-[2-(4-morpholino)ethyl]acetate (4.2 g, 16.28 mmol)is dissolved in 6N hydrochloric acid (100.0 mL), and the reaction isrefluxed for 4.5 hours. The water is then evaporated, and the product isazeotroped dry using toluene to give2-amino-2-[2-(4-morpholino)ethyl]acetic acid dihydrochloride.

2-Amino-2-[2-(4-morpholino)ethyl]acetic acid dihydrochloride (4.0 g,15.33 mmol) is dissolved in a solution of methanol (100.0 mL) and acetylchloride (5.0 mL), and the reaction is refluxed for 24 hours. Thesolvent is then evaporated to give methyl 2-amino-2-[2-(4-morpholino)ethyl]acetate dihydrochloride.

Methyl 2-amino-2-[2-(4-morpholino)ethyl]acetate dihydrochloride (6.0 g,21.82 mmol) is dissolved in chloroform (110.0 mL) and triethylamine(9.12 mL, 65.46 mmol). To this solution is added4-methoxybenzenesulfonyl chloride (4.51 g, 21.82 mmol), and the reactionis refluxed for 4 hours. After cooling, the reaction is diluted withmore chloroform, washed with sainted sodium bicarbonate, the organiclayer is dried (Na₂ SO₄), and the solvent is evaporated to give methyl2-(4-methoxybenzenesulfonyl)-amino-2-[2-(4-morpholino)ethyl]acetate.

To a suspension of sodium hydride (1.03 g, 21.5 mmol) indimethylformamide (108.0 mL), is added methyl2-(4-methoxybenzenesulfonyl)amino-2-[2-(4-morpholino)ethyl]acetate (8.0g, 21.5 mmol) in dimethylformamide (10.0 mL). After stirring at roomtemperature for 30 minutes, benzyl bromide (2.56 mL, 21.5 mmol) isadded, and the reaction is stirred overnight at room temperature. Thereaction is then partitioned between ethyl acetate and acidic water(pH=˜5), the organic layer is dried (Na₂ SO₄), and the solvent isevaporated. The product is purified by silica gel chromatography (3%methanol/methylene chloride) to give methyl2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]acetate.

Methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]acetate (7.33 g, 15.86 mmol) is dissolved in methanol (80.0 mL).To this solution is added sodium hydroxide (17.5 mL of a 1N aqueoussolution, 17.5 mmol), and the reaction is stirred at room temperaturefor 8 hours. The reaction is then acidified to pH=˜3 using 2.5Nhydrochloric acid, and then the solvent is evaporated. The residue issuspended in ethanol, the inorganic salts are faltered away, and thefiltrate is evaporated to give2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]aceticacid hydrochloride.

2-[[4-Methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-morpholino)ethyl]aceticacid hydrochloride (4.24 g, 8.75 mmol), 1-hydroxybenzotriazole (1.34 g,8.75 mmol), 4-methylmorpholine (3.85 mL, 35.02 mmol), andO-t-butylhydroxylamine hydrochloride (1.10 g, 8.75 mmol) are dissolvedin methylene chloride (44.0 mL), and the reaction is cooled to 0° C. Tothis solution is added N-[dimethylaminopropyl-N'-ethylcarbodiimidehydrochloride (3.35 g, 17.5 mmol), and the reaction is allowed to warmup to room temperature and stir overnight. The reaction is diluted withmore methylene chloride, and the organic layer is washed with saturatedsodium bicarbonate, brine, dried (MgSO₄), and the solvent is evaporated.The product is purified by silica gel chromatography (2%methanol/methylene chloride) to giveN-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-2-[2-(4-morpholino)ethyl]acetamide.

EXAMPLE 8

The following compounds are prepared similarly to example 7:

(a)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl)amino]-2-[2-(4-morpholino)ethyl]acetamide,m.p. 62°-64° C., using isobutyl bromide in the alkylation step in placeof benzyl bromide.

(b)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-picolyl)amino]-2-[2-(4-morpholino)ethyl]acetamidedihydrochloride, m.p. 195°-197° C., using 2-picolyl chloride in thealkylation step in place of benzyl bromide.

(c)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[2-(4-morpholino)ethyl]acetamidedihydrochloride, m.p. >210° C., using 3-picolyl chloride in thealkylation step in place of benzyl bromide.

(d)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-methylthiazol-4-ylmethyl)amino]-2-[2-(4-morpholino)ethyl]acetamidedihydrochloride, m.p. 180° C., using 4-chloromethyl-2-methylthiazole inthe alkylation step in place of benzyl bromide.

(e)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-(4-thiomorpholino)ethyl]acetamide,m.p. 50°-52° C., by starting the synthesis withN-(2-chloroethyl)thiomorpholine, and carrying out the subsequent stepsas described in example 7.

(f)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[2-methylthiazol-4-ylmethyl]acetamide,m.p. 79°-81° C., by starting the synthesis with4-chloromethyl-2-methylthiazole hydrochloride, and carrying out thesubsequent steps as described in example 7.

(g)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[6-chloropiperonyl]acetamide,m.p. 70°-74° C., by starting the synthesis with 6-chloropiperonylchloride, and carrying out the subsequent steps as described in example7.

(h)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(1-pyrazolyl)methyl]acetamide,m.p. 130°-131° C., by starting the synthesis with β-pyrazol-1-yl-alanine(prepared following the procedure of J. Am. Chem. Soc., 110, p. 2237(1988)), and carrying out the subsequent steps as described in example7.

(i)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[3-picolyl]acetamidedihydrochloride, m.p. >220° C., by starting the synthesis with 3-picolylchloride, and carrying out the subsequent steps as described in example7, but in addition, using 3-picolyl chloride in the alkylation step inplace of benzyl bromide in example 7.

(j)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamidehydrochloride, m.p. >200° C., by starting the synthesis withN-τ-methylhistidine dihydrochloride (prepared following the procedure ofRecueil, 97, p.293 (1978)), and carrying out the subsequent steps asdescribed in example 7.

(k)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl)amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamidehydrochloride, m.p. 194°-195° C., by starting the synthesis withN-τ-methylhistidine dihydrochloride and carrying out the subsequentsteps as described in example 7, using isobutyl iodide in the alkylationstep in place of benzyl bromide.

(l)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamidehydrochloride, m.p. >220° C., by starting the synthesis withN-τ-methylhistidine dihydrochloride and carrying out the subsequentsteps as described in example 7, using 3-picolyl chloride in thealkylation step in place of benzyl bromide.

(m)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-picolyl)amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamidehydrochloride, m.p. 162°-164° C., by starting the synthesis withN-τ-methylhistidine dihydrochloride and carrying out the subsequentsteps as described in example 7, using 2-picolyl chloride in thealkylation step in place of benzyl bromide.

(n)N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-methylthiazol-4-ylmethyl)amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamidehydrochloride, m.p. 160°-163° C., by starting the synthesis withN-τ-methylhistidine dihydrochloride and carrying out the subsequentsteps as described in example 7, using 4-chloromethyl-2-methylthiazolein the alkylation step in place of benzyl bromide.

(o)N-hydroxy-2-[[4-methoxybenzenesulfonyl](piperonyl)amino]-2-[(1-methyl-4-imidazolyl)methyl]acetamidehydrochloride, m.p. 195° C., by starting the synthesis withN-τ-methylhistidine dihydrochloride and carrying out the subsequentsteps as described in example 7, using piperonyl chloride in thealkylation step in place of benzyl bromide.

EXAMPLE 9

(a) Methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (2.1 g,6.01 mmol) is dissolved in methanol (20.0 mL). To this solution is addedhydroxylamine hydrochloride (0.84 g, 12.0 mmol), followed by theaddition of sodium methoxide (7.0 mL of a 4.37M solution). The reactionis stirred overnight at room temperature. The reaction is worked up byfirst removing all the solvent, and partitioning between ethylacetate/hexane (2/1) and saturated sodium bicarbonate. The aqueous phaseis extracted well with ethyl acetate/hexane, the combined organic layersare dried (MgSO₄), and the solvent is evaporated. The product ispurified by silica gel chromatography (ethyl acetate) to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionamide, m.p.149°-151° C.

The starting material is prepared as follows:

D,L-Alanine (27.0 g, 300.0 mmol) is dissolved in a solution of methanol(100.0 mL) saturated with HCl gas, and the reaction is refluxed for 2hours. The solvent is then evaporated, and the residue triturated withethyl acetate to give alanine methyl ester hydrochloride.

Alanine methyl ester hydrochloride (7.0 g, 50.0 mmol) is dissolved inmethylene chloride (100.0 mL) and triethylamine (20.0 mL, 143.0 mmol).To this solution is added 4-methoxybenzenesulfonyl chloride (10.3 g,50.0 mmol), and the reaction is stirred at room temperature briefly. Thereaction is made basic with 1N sodium hydroxide, and washed withmethylene chloride. The combined organic layers are dried (Na₂ SO₄), andthe solvent is evaporated. Hexane is added to the residue and theprecipitate is collected to give N-[4-methoxybenzenesulfonyl]-alaninemethyl ester.

To a suspension of sodium hydride (0.60 g, 11.0 mmol) indimethylformamide (20.0 mL), is addedN-[4-methoxybenzenesulfonyl]-alanine methyl ester (2.6 g, 10.0 mmol) indimethylformamide (10.0 mL). After stirring at room temperature for 30minutes, benzyl bromide (1.22 mL, 10.0 mmol) is added, and the reactionis stirred for two hours at room temperature. The reaction is thenpartitioned between ether and brine, the organic layer is dried (Na₂SO₄), and the solvent is evaporated. The product is purified by silicagel chromatography (20% ether/hexanes) to give methyl2-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-propionoate.

(b) Similarly prepared isN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-thiomethylbutyramide,m.p. 104°-106° C., by starting the synthesis with D,L-methionine, andcarrying out the subsequent steps as described above.

EXAMPLE 10

A solution of methyl2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(methylsulfonyl)butyrate(900 mg, 2.0 mmol), sodium methoxide previously generated from sodiummetal spheres (100.0 mg, 4.5 mmol), and hydroxylamine hydrochloride(280.0 mg, 4.0 mmol) is refluxed for 2 days. The mixture is cooled toroom temperature, concentrated in vacuo, diluted with water, acidifiedwith citric acid, and extracted with ethyl acetate. The combined organicextracts are dried (MgSO₄) and and the solvent is evaporated. Theproduct is purified by silica gel chromatography (ethyl acetate) to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(methylsulfonyl)butyramide,[M+1]=157.

The starting material is prepared as follows:

To a solution of racemic methionine methyl ester (1.98 g, 10.0 mmol) inmethylene chloride (25 mL) containing triethylamine (2.0 mL, 14.3 mmol)is added 4-methoxy-benzenesulfonyl chloride (2.1 g, 10.2 mmol). Afterstirring for 2 hours at room temperature, the mixture is diluted with 1N hydrochloric acid. The organic layer is removed and the aqueous layeris extracted with ether. The combined organic layers are washed withbrine, dried (MgSO₄), and and the solvent is evaporated. Theconcentrated solution is triturated with ether, and the product iscollected by filtration to give methyl2-[[4-methoxybenzenesulfonyl]amino]-4-(thiomethyl)butyrate.

To a solution of methyl2-[[4-methoxybenzenesulfonyl]amino]-4-(thiomethyl)butyrate (2.1 g, 6.2mmol) in dimethylformamide (15 mL) containing potassium carbonate (4.0g, 29.0 mmol) is added benzyl bromide (1.5 mL, 12.6 mmol). The reactionmixture is stirred for 1 hour at room temperature. The mixture isquenched with water and extracted with ether. The organic extracts arewashed with brine, dried (MgSO₄), and and the solvent is evaporated. Theproduct is purified by silica gel chromatography (30% ethylacetate/hexanes) to give methyl2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(thiomethyl)butyrate.

A solution of methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(thiomethyl)butyrate (925.0 mg, 2.17 mmol) in 25% peraceticacid (5 mL) is stirred overnight at room temperature. The mixture isconcentrated in vacuo, diluted with water, and extracted with ethylacetate. The combined organic extracts are dried (MgSO₄) and the solventis evaporated to give methyl2-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-(methylsulfonyl)butyrate.

EXAMPLE 11

(a) To a solution of2R-[[(4-methoxybenzene)sulfonyl](benzyl)amino]propionic acid (1.04 g,2.98 mmol) in methylene chloride (50 mL) containing dimethylformamide(230 mL, 2.98 mmol) at room temperature is added oxalyl chloride (520mL, 5.96 mmol) over 5 minutes dropwise. The mixture is stirred for 30minutes at room temperature, then added to a pre-formed mixture ofhydroxylamine hydrochloride (828 mg, 11.92 mmol) and triethylamine (2.5mL, 17.9 mmol) in tetrohydrofuran (20 mL)/water (1.5 mL) at 0° C. Thereaction mixture is stirred for 45 minutes at 0° C. then slowly warmedto room temperature for 15.5 hours. The mixture is acidified with 1Nhydrochloric acid and extracted with methylene chloride. The combinedorganic extracts are washed with brine, dried (MgSO₄), and the solventis evaporated. The crude product is recrystallized from diethylether/ethyl acetate (1:1) to giveN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-propionamide,m.p. 127°-129° C.

The starting material is prepared as follows:

To a solution of D-alanine methyl ester hydrochloride (3.0 g, 21.5 mmol)in methanol (10 mL) is added benzaldehyde (2.3 mL, 22.6 mmol). Thereaction mixture is stirred at room temperature for 3 hours. The solventis then evaporated. To the resultant residue is added acetic acid (15mL) and methanol (1 mL) followed by portionwise addition of sodiumcyanoborohydride (1.35 g, 21.5 mmol) at room temperature. The mixture isstirred overnight, and then the solvent is evaporated. The remainingresidue is diluted with water (75 mL) and basified with Na₂ CO₃. Themixture is extracted with ethyl acetate (3x75 mL). The combined organicextracts are washed with brine (50 mL), dried (Na₂ SO₄), and the solventis evaporated to give N-benzyl-D-alanine methyl ester.

To a solution of N-benzyl-D-alanine methyl ester (˜2 g) in methylenechloride (40 mL) containing triethylamine (2.47 mL, 17.7 mmol) is added4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol). The reactionmixture is stirred overnight at room temperature. The mixture isacidified with 1N HC₁ and extracted with methylene chloride. Thecombined organic extracts are washed with brine, dried (Na₂ SO₄), andthe solvent is evaporated. The crude product is purified by silica gelchromatography (10%->20% ethyl acetate/hexanes) to provide methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino] propionate.

To a solution of methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (1.05 g, 2.89 mmol) in tetrahydrofuran (60 mL) at roomtemperature is added 1N aqueous sodium hydroxide (8.6 mL, 8.67 mmol).The reaction mixture is stirred for 19 hours at room temperature. Thetetrahydrofuran is then evaporated. The remaining residue is acidifiedwith 1N hydrochloric acid and extracted with ethyl acetate. The combinedorganic extracts are washed with brine, dried (Na₂ SO₄), and the solventis evaporated to give2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionic acid.

(b) Similarly prepared isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-benzylacetamide,[M+1]=441, by starting with (R)-phenylalanine, and carrying out thepreviously described steps.

EXAMPLE 12

(a) To a solution ofN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl(benzyl)-amino]-6-(N,N-dimethylamino)-hexamide(2.13 g, 4.21 mmol) in 1,2-dichloroethane (140 mL) is added ethanol (250mL, 4.21 mmol). The solution is cooled to -10° C. and hydrogen chloridegas is bubbled in for 30 minutes. The reaction mixture is then sealedand allowed to warm to room temperature, stirring for 2 days. At thistime point, the reaction mixture is cooled to -10° C. and hydrogenchloride gas is bubbled in for an additional 30 minutes. The reactionmixture is sealed, warmed to room temperature, and stirred for 24 hours.The mixture is reduced in volume by 1/2 in vacuo and triturated withether. The mother liquid is removed and the remaining white solid isdried in vacuo to provideN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)-amino]-6-(N,N-dimethylamino)-hexanamidehydrochloride salt, m.p. 175°-177° C.

The starting material is prepared as follows:

To a solution of ε--N--CBZ--(R)-lysine methylester hydrochloride (15.0g, 45.10 mmol) in methylene chloride (250 mL) containing triethylamine(15.72 mL, 112.75 mmol) is added 4-methoxybenzenesulfonyl chloride(10.25 g, 49.61 mmol) at 0° C. The reaction mixture is warmed to roomtemperature and stirred overnight. The reaction mixture is diluted withmethylene chloride and washed with 1N hydrochloric acid. The organiclayer is washed with brine, dried (Na₂ SO₄), and concentrated in vacuoto yield a yellow oil. The product is purified by silica gelchromatography (50% ethyl acetate/hexanes) to give methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-6-(N-benzylcarbamoyl) hexanoate.

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-6-(N-benzylcarbamoyl) hexanoate(12.4 g, 26.5 mmol) in dimethylformamide (100 mL) is added potassiumcarbonate (7.5 g, 52 mmol) and benzyl bromide (3.3 mL, 28.0 mmol), andthe reaction is stirred for 24 hours at room temperature. The mixture ispartitioned between water and 50% diethyl ether/ethyl acetate. Theaqueous layer is removed and extracted with 50% diethyl ether/ethylacetate. The combined organic layers are washed with brine, dried(MgSO₄) and the solvent is evaporated. The crude product is purified bysilica gel chromatography (50% ethyl acetate/hexanes) to give methyl2(R)-[[4-methoxybenzene-sulfonyl](benzyl)amino]-6-(N-benzylcarbamoyl)hexanoate.

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(benzylcarbamoyl)hexanoate (8.61 g, 15.53 mmol) in 95% ethanol (150 mL) is added 1Nhydrochloric acid (15.5 mL, 15.53 mmol) followed by 10% Pd/C (4.0 g).The reaction mixture is stirred at room temperature under 1 atmosphereof hydrogen gas for 2 hours. The mixture is filtered through Celite andthe solvent is evaporated to provide methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-aminohexanoate.

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-aminohexanoate (5.05 g,12.02 mmol) in refluxing formic-acid (120 mL) containing sodium formate(2.45 g, 36.07 mmol) is added 37% aqueous formaldehyde (2.70 mL, 36.07mmol). While continuing to reflux the reaction mixture, three morealiquots of 37% aqueous formaldehyde (2.70 mL, 36.07 mmol each aliquot)are added at 10 minute intervals. The mixture is concentrated in vacuoto yield a yellow oil. The crude product is purified by silica gelchromatography (10:1:0.5; ethylacetate/methanol/ammonium hydroxide) toprovide methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino)hexanoate. This procedure is repeated and the combined product is usedin the next reaction.

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino)hexanoate (4.55 g, 10.7 mmol) in tetrahydrofuran (100 mL) is added 1Naqueous lithium hydroxide (20 mL, 20.33 mmol). The reaction mixture isstirred at room temperature overnight. The reaction mixture is directlyconcentrated to dryness in vacuo to give the lithium salt of2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino)hexanoic acid.

To a solution of2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino)hexanoic acid lithium salt (4.42 g, 10.18 mmol) in methylene chloride(100 mL) containing N- methylmorpholine (6.73 mL, 61.06 mmol),1-hydroxybenzotriazole monohydrate (1.64 g, 10.687 mmol) andO-t-butylhydroxyl amine hydrochloride (1.41 g, 11.20 mmol) is addedN-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.90 g,20.36 mmol) at 0° C. The reaction mixture is allowed to warm to roomtemperature and stirring is continued overnight. The mixture is dilutedwith methylene chloride, washed with saturated sodium bicarbonate, thenwith brine, dried (Na₂ SO₄) and the solvent is evaporated. The crudeproduct is purified by silica gel chromatography (10:1:0.5 ethylacetate/methanol/ammonium hydroxide) to provideN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-(N,N-dimethylamino)hexanamide.

(b) Similarly prepared isN-hydroxy-2-(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-6-(N,N-dimethylamino)-hexanamidedihydrochloride, m.p. 179°-180° C.

The first step is carried out as described above. The alkylation step iscarried out as follows:

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-6-(benzylcarbamoyl)-hexanoate(10.48 g, 22.43 mmol) in dimethylformamide (220 mL) at 0° C. is added3-picolyl chloride hydrochloride (3.86 g, 23.55 mmol) followed by sodiumhydride (2.24 g, 56.07 mmol, 60% in oil). The reaction mixture is warmedto room temperature and stirred for 24 hours. The reaction mixture isquenched with water and extracted with ethyl acetate. The combinedorganic extracts are washed with brine, dried (Na₂ SO₄), and the solventis evaporated. The crude product is purified by silica gelchromatography (75% ethyl acetate/hexanes) to provide methyl2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-6-(benzylcarbamoyl)hexanoate.

All of the following steps are carded out as described above.

(c) Similarly prepared isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](2-picolyl)-amino]-6-(N,N-dimethylamino)-hexanamidedihydrochloride, m.p. 134°-136° C., by alkylating with 2-picolylchloride in the second step and carrying out the subsequent steps asdescribed above.

EXAMPLE 13

N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanamide(2.17 g, 3.86 mmol) is dissolved in dichloroethane (12 mL) containingethanol (0.22 mL, 3.86 mmol), and the reaction is cooled to -10° C.Hydrochloric acid gas is bubbled through this solution for 30 minutes.The reaction is sealed, warmed to room temperature and stirred for 2days. The solvent is reduced to 1/2 volume by evaporating solvent, andtriturated with ether. The resulting solid is removed and dried in vacuoto provideN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanamidehydrochloride, m.p. 105°-108° C.

The starting material is prepared as follows:

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-amino hexanoatehydrochloride (7.5 g, 16.44 mmol) in methylene chloride (170 mL) isadded 1-hydroxybenzotriazole monohydrate (2.64 g, 1726 mmol),N-methylmorpholine (5.44 mL, 49.34 mmol), and N,N-dimethylglycine (1.86g, 18.08 mmol), and the reaction is cooled to 0° C.N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (6.30 g,32.88 mmol) is added at 0° C. The reaction mixture is warmed to roomtemperature and stirred overnight. The mixture is diluted with methylenechloride and washed with saturated aqueous sodium bicarbonate, and thenwith brine. The organic layer is dried (Na₂ SO₄), filtered, and and thesolvent is evaporated. The crude product is purified by silica gelchromatography (10/0.5/0.5 ethyl acetate/methanol/ammonium hydroxide) toprovide methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanoate(6.04 g).

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanoate(3.95 g, 7.82 mmol) in tetrahydrofuran (75 mL) at 0° C. is added 1Nlithium hydroxide (15.64 ml, 15.64 mmol). The reaction mixture is warmedto room temperature and stirred overnight. The tetrahydrofuran isremoved and the remaining aqueous layer is acidified with 1Nhydrochloric acid. The mixture is evaporated to dryness to yield2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanoicacid hydrochloride.

To a solution of2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanoicacid hydrochloride (4.12 g, 7.82 mmol) in methylene chloride (78 mL) anddimethylformamide (5 mL) is added 1-hydroxybenzotriazole monohydrate(1.26 g, 8.21 mmol), N-methylmorpholine (2.58 ml, 23.45 mmol), andO-t-butyhydroxylamine hydrochloride (1.08 g, 8.60 mmol). The reaction iscooled to 0° C., and N-[dimethylaminopropyl]-N'-ethylcarbodiimidehydrochloride (3.0 g, 15.64 mmol) is added. The reaction mixture iswarmed to room temperature and stirred overnight. The mixture is thendiluted with methylene chloride and washed with saturated aqueous sodiumbicarbonate, and then with brine. The organic layer is dried (Na₂ SO₄),filtered, and and the solvent is evaporated. The crude product ispurified by silica gel chromatography (10/0.5/0.5 ethylacetate/methanol/ammonium hydroxide) to provideN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino]hexanamide.

EXAMPLE 14

(a) To a solution of4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carboxy-tetrahydrothiopyran(413.0 mg, 1.0 mmol) in methylene chloride (10 mL) containingdimethylformamide (80.0 mg, 1.1 mmol) is added a 2N solution of oxalylchloride in methylene chloride (1.0 ml, 2.0 mmol) at -10° C. The mixtureis allowed to warm to 20° C. for 30 minutes. This mixture is added to apre-stirred mixture of hydroxylamine hydrochloride (280.0 mg, 4.0 mmol)in tetrahydrofuran (10 ml)/water (1 ml) containing triethylamine (650.0mg, 6.0 mmol) at 0° C. dropwise. The reaction mixture is allowed toslowly warm to room temperature and stirring is continued for 1.5 days.The reaction is worked up by partitioning between 1N hydrochloric acidand ethyl acetate. The aqueous layer is removed and repeatedly extractedwith ethyl acetate. The combined organic layers am dried (Na₂ SO₄) andthe solvent is evaporated. The crude product is purified by silica gelchromatography (2% methanol/methylene chloride) to give4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-tetrahydrothiopyran,m.p. 179°-181° C.

The starting material is prepared as follows:

A solution of tetrahydrothiopyran-4-one (4.64 g, 40.0 mmol) in methanol(10 mL) is added to a mixture of sodium cyanide (2.0 g, 40.0 mmol) andammonium chloride (2.36 g, 44.0 mmol) in water (8 mL). The reactionmixture is heated to reflux for 14 hours. The mixture is diluted withwater, basified with potassium carbonate, and extracted with diethylether. The organic extract is dried (MgSO₄) and filtered. The solutionis acidified with hydrochloric acid saturated with methylene chloride.The resulting precipitate is filtered off providing4-amino-4-cyano-tetrahydrothiopyran hydrochloride salt.

A solution of 4-amino-4-cyano-tetrahydrothiopyran (5.4 g, 30.3 mmol) in6N aqueous hydrochloric (250 mL) acid is heated to reflux for 24 hours.The mixture is triturated by addition of methanol/toluene, and filtered.To the crude product, 4-amino-4-carboxytetrahydrothiopyran is added 40ml of methanol followed by careful addition of thionyl chloride (3.0 ml,41.1 mmol). The reaction mixture is heated to reflux for 12 hours,cooled to room temperature, and concentrated in vacuo to a reducedvolume. The remaining mixture is triturated with ethyl acetate/diethylether, and the product is collected by filtration, to give4-amino-4-carbomethoxy-tetrahydrothiopyran hydrochloride.

To a solution of 4-amino-4-carbomethoxy-tetrahydrothiopyranhydrochloride (3.1 g, 15.0 mmol) in methylene chloride (75 mL)containing triethylamine (3.5 g, 330.0 mmol) is added4-methoxybenzenesulfonyl chloride (4.1 g, 20.0 mmol) at roomtemperature. The reaction mixture is stirred at room temperature for 18hours. The mixture is diluted with water and the organic layer isremoved. The aqueous layer is extracted with diethyl ether and theorganic extracts are washed with brine, dried (MgSO₄) and the solvent isevaporated. The product is purified by silica gel chromatography (50%ethylacetate/hexanes) to provide4-[[4-methoxybenzenesulfonyl]amino]-4-carbomethoxy-tetrahydrothiopyran.

To a solution of4-[[(4-methoxybenzene)sulfonyl]amino]-4-carbomethoxy-tetrahydrothiopyran(690.0 mg, 2.0 mmol) in dimethylformamide (20 mL) at 0° C. is addedsodium hydride (100.0 mg, 2.5 mmol, 60% in oil) and benzyl bromide (0.5ml, 4.2 mmol). The reaction mixture is allowed to warm to roomtemperature and stirred for 16 hours. The mixture is quenched byaddition of water and extracted with 50% ethyl acetate/diethyl ether.The combined organic extracts are dried (MgSO₄), filtered, and thesolvent is evaporated. The product is purified by silica gelchromatography (50% diethyl ether/hexanes) to provide4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carbomethoxy-tetrahydrothiopyran.

To a solution of4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carbomethoxy-tetrahydrothiopyran(800.0 mg, 1.9 mmol) in methanol (50 mL) is added 1N sodium hydroxide(25 mL). The mixture is heated to reflux for 10 hours, and then solidsodium hydroxide is added (3.0 g, excess) and refluxing is continued for18 hours. The mixture is concentrated to a volume of approximately 30 mLand acidified with citric acid (pH=5). The mixture is partitionedbetween ethyl acetate and water. The organic layer is removed, washedwith brine, dried (MgSO₄), and the solvent is evaporated to give4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carboxytetrahydrothiopyran.

(b) Similarly prepared is4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-tetrahydropyran,m.p. 137°-140° C., by starting with tetrahydropyran-4-one in the firststep, and carrying out the subsequent steps as described above.

(c) Similarly prepared is1-[N-hydroxy-carbamoyl]-1-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-cyclohexane,m.p. 149°-151° C., by using commercially available1-amino-cyclohexanecarboxylic acid in the second step, and carrying outthe subsequent steps as described above.

(d) Similarly prepared is1-[N-hydroxy-carbamoyl]-1-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-cyclopentane,m.p. 67.0°-68.0° C., by using commercially available 1-aminocyclopentanecarboxylic acid in the second step, and carrying out the subsequentsteps as described above.

(e) Similarly prepared is1-[N-hydroxy-carbamoyl]-1-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-cyclohexane,m.p. 115° C., by using 1-aminocyclohexanecarboxylic acid in the secondstep, alkylating-[carbomethoxy]-1-[[(4-methoxybenzene)sulfonyl]amino]-cyclohexane with3-picolyl chloride in the third step, and carrying out the other stepsas described above.

(f) Similarly prepared is1-[N-hydroxy-carbamoyl]-1-[[4-methoxybenzenesulfonyl]-(3-picolylamino]-cyclopropanehydrochloride, m.p. 205°-207° C., starting with1-amino-1-cyclopropanecarboxylic acid.

EXAMPLE 15

4-[N-t-Butyloxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]piperidineis dissolved in dichloroethane (60 mL) and ethanol (1.0 mL) in a glasssealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbledthrough the solution for 30 minutes at -10° C. The tube is sealed,gradually warmed to room temperature, and stirred overnight. At thispoint, hydrochloric acid gas is again bubbled through the reactionmixture as done previously and stirred at room temperature for anadditional 24 hours. The reaction mixture is reduced to 1/3 volume invacuo and triturated with diethyl ether. The solid is filtered off anddried in vacuo to provide4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-piperidine,m.p. 135.5°-142° C.

The starting material is prepared as follows:

A mixture of N-carboethoxy-4-piperidone (88.6 g, 517.2 mmol), sodiumcyanide (30.0 g, 612.1 mmol) in water (54 mL), ammonium chloride (34.0g, 635.5 mmol) in water (72 mL), and ammonium hydroxide (76 ml) isheated to 60°-65° C. for 5 hours, and then stirred at room temperatureovernight. The resulting solid is filtered off, dissolved in methylenechloride, and washed with a small amount of brine. The organic layer isdried (MgSO₄), concentrated in vacuo to 1/2 volume, and triturated withhexane. The resulting precipate is collected by filtration and driedunder vacuum, to give N-carboethoxy-4-amino-4-cyanopiperidine.

A solution of N-carboethoxy-4-amino-4-cyanopiperidine (82.0 g) in water(700 mL) containing concentrated hydrochloric acid (800 mL) is stirredat room temperature for 4 days. The solvent is then evaporated to give4-amino-4-carboxypiperidine dihydrochloride.

Into a heterogeneous mixture of 4-amino-4-carboxypiperidinedihydrochloride (61.0 g, 0.34 mmol) in methanol (600 mL) is bubbledhydrogen chloride gas at room temperature. The reaction mixture isconcentrated to dryness in vacuo, dissolved in 1,4-dioxane (200 mL), andconcentrated in vacuo. The residue is redissolved in methanol (1600 mL)into which hydrogen chloride gas is bubbled for 45 minutes. The reactionmixture is refluxed for 18 hours. Most of the solvent is thenevaporated, the product is collected by filtration, and washed withethyl acetate to give 4-amino-4-carbomethoxypiperidine dihydrochloride.

To a mixture of 4-amino-4-carbomethoxypiperidine dihydrochloride (6.60g, 28.7 mmol) and potassium carbonate (18.8 g, 143.5 mmol) indioxane/water (350 ml/176 ml) at 0° C. is added di-t-butyl-dicarbonate(8.14 g, 37.31 mmol) in dioxane (60 mL) over 2 hours. The reactionmixture is warmed to room temperature and stirred for 8 hours. To thismixture is added a solution of 4- methoxybenzenesulfonyl chloride (7.71g, 37.31 mmol) in dioxane (60 mL) at 0° C. The reaction mixture isstirred at room temperature overnight. An additional portion of 4-methoxybenzenesulfonyl chloride (7.71 g, 37.31 mmol) in dioxane (60 mL)is added to the mixture at 0° C. The reaction mixture is allowed to warmto room temperature and stirred overnight. The mixture is concentratedin vacuo, diluted with water, and extracted with ethyl acetate. Theaqueous layer is removed, saturated with sodium chloride, andre-extracted with ethyl acetate. The combined extracts are dried(MgSO4), and the solvent is evaporated. The crude product is purified bysilica gel chromatography (50% ethylacetate/hexane) to provide4-[[4-methoxybenzenesulfonyl]-amino]-1-[(t-butoxycarbonyl]-4-[carbomethoxy]-piperidine,contaminated with a small amount of 4-methoxybenzene-sulfonic acid.

To a solution of4-[[4-methoxybenzenesulfonyl]amino]-1-[(t-butoxycarbonyl]-4-[carbomethoxy]-piperidine(4.0 g, 9.30 mmol) in dimethylformamide (150 mL) at 0° C. is addedsodium hydride (1.12 g, 28.0 ml, 60% in oil) followed by benzyl bromide(4.8 g, 28.0 mmol). The reaction mixture is allowed to warm to roomtemperature for 1 hour. The mixture is quenched with water and extractedwith diethyl ether. The organic extract is dried (MgSO₄) and the solventis evaporated. The crude product is purified by silica gelchromatography (50% ethyl acetate/hexanes) to provide4-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-1-[(t-butoxycarbonyl]-4-[carbomethoxy]piperidine.

To a solution of4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[(t-butoxycarbonyl]-4-[carbomethoxy]-piperidine(1.8 g, 3.47 mmol) in ethyl acetate (10 mL) is added a hydrogen chloridegas saturated methylene chloride solution (15 mL). The reaction mixtureis stirred for 4 hours at room temperature. The mixture is concentratedin vacuo to give4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-[carbomethoxy]-piperidine.

To a solution of4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-[carbomethoxy]-piperidine(1.0 g, 2.39 mmol) in dimethylformamide (160 mL) is added sodium hydride(287.0 mg, 7.18 mmol, 60% in oil) at 0° C., followed by benzyl bromide(450.0 mg, 2.63 mmol). The reaction mixture is slowly warmed to roomtemperature and stirred overnight.

The mixture is quenched with water and extracted with ethyl acetate. Thecombined organic layers are washed with brine, dried (Na₂ SO₄) and thesolvent is evaporated to give4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carbomethoxy]-piperidine.

A heterogeneous mixture of4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carbomethoxy]-piperidine(1.2 g, 2.26 mmol) in 50% aqueous sodium hydroxide (10 mL) and methanol(50 mL) is heated to reflux for 16 hours. The methanol is evaporated andthe residue is neutralized with 4N hydrochloric acid. The aqueoussolution is extracted with ethyl acetate. The combined organic extractsare dried (NaSO₄) and the solvent is evaporated to give4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carboxyl-piperidine.

To a mixture of4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carboxy]-piperidine(850.0 mg, 1.64 mmol) in methylene chloride (100 mL) containingN-methylmorpholine (0.6 ml, 5.48 mmol) and O-t-butylhydroxyl aminehydrochloride (620.0 mg, 4.94 mmol) is addedN-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.1 g, 5.74mmol). The reaction mixture is stirred overnight at room temperature.The mixture is diluted with water and extracted with methylene chloride.The combined organic extracts are dried (Na₂ SO₄) and the solvent isevaporated. The crude product is purified by silica gel chromatography(ethyl acetate) to provide4-[N-t-butyloxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-piperidine.

Alternately, 4-[[4-methoxybenzenesulfonyl]amino]-1-[(t-butoxycarbonyl]-4-carbomethoxy]-piperidine isfirst hydrolyzed with sodium hydroxide to4-[[4-methoxybenzenesulfonyl]amino]-1-[(t-butoxycarbonyl]-4-[carboxy]-piperidine.Treatment with O-t-butylhydroxylamine under conditions described abovegives4-[N-t-butyloxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[t-butoxycarbonyl]-piperidine. Reaction with 1N hydrochloric acid in ethyl acetate yields4-[N-t-butyloxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-piperidine,which is treated with benzyl bromide as described above.

Similarly prepared, starting from4-[[4-methoxybenzenesulfonyl(benzyl)amino]-4-[carbomethoxy]-piperidine,are the following:

(a)4-[N-Hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)-amino]-1-[dimethylaminoacetyl]-piperidinehydrochloride, m.p. 145° C.;

(b)4-[N-Hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl(benzyl)-amino]-1-[3-picolyl]-piperidinedihydrochloride, m.p. 167° C.;

(c)4-[N-Hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)-amino]-1-[carbomethoxymethyl]-piperidinehydrochloride, m.p. 183.5°-185° C.;

(d)4-[N-Hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)-amino]-piperidinetrifluoroacetate;

(e)4-[N-Hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)-amino]-1-[t-butoxycarbonyl]-piperidine;

(f)4-[N-Hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)-amino]-1-[methylsulfonyl]-piperidine;

(g)4-[N-Hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[methyl]piperidinehydrochloride, m.p. 185.5°-187° C.;

(h)4-[N-Hydroxycarbamoyl]-4-[[methoxybenzenesulfonyl](benzyl)amino]-1-[morpholinocarbonyl]piperidine,m.p. 89°-91° C.;

(i)4-[N-Hydroxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[4-picolyl]piperidinedihydrochloride, m.p. 168° C.

EXAMPLE 16

Ethyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetate (11.20 g, 0.9mmol) is dissolved in methanol (100 mL). To this solution is addedhydroxylamine hydrochloride (4.31 g, 62.0 mmol), followed by theaddition of sodium methoxide, freshly prepared from sodium (2.14 g, 93.0mmol) dissolved in methanol (55 mL). The reaction is stirred overnightat room temperature. The reaction is worked up by partitioning betweendilute hydrochloric acid (pH=˜3) and ethyl acetate. The aqueous phase isextracted well with ethyl acetate, the combined organic layers are dried(Na₂ SO₄), and the solvent is evaporated. The product is purified bysilica gel chromatography (75% ethyl acetate/hexane) to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-acetamide, m.p.112°-114° C.

The starting material is prepared as follows:

Benzylamine (16.0 mL, 145.2 mmol) is dissolved in chloroform (110 mL),and the solution is cooled to 0° C. To this solution is added4-methoxybenzenesulfonyl chloride (10.0 g, 48.4 mmol). The reaction isstirred at room temperature for 1 hour, and then refluxed for 1 hour.After cooling back to room temperature, the reaction is washed threetimes with 4N hydrochloric acid (200 mL), twice with water (100 mL),once with brine (50 mL), then dried (Na₂ SO₄), and the solvent isevaporated to give N-[4-methoxybenzenesulfonyl]-benzylamine.

Sodium hydride (1.56 g of a 50% oil dispersion, 33.0 mmol) is suspendedin tetrahydrofuran (85 mL). To this is added a solution ofN-[4-methoxybenzenesulfonyl]-benzylamine (9.0 g, 32.5 mmol) also intetrahydrofuran (85 mL), and the reaction is stirred for 30 minutes atroom temperature. Then ethyl bromoacetate (5.40 mL, 48.8 mmol) is added,and the reaction is stirred overnight at room temperature. The reactionis quenched with a small amount of water, and all the solvent isremoved. The crude mixture is partitioned between ethyl acetate andwater, the aqueous phase is extracted several times with ethyl acetate,the combined organic layers are dried (Na₂ SO₄), and the solvent isevaporated. The product is purified by silica gel chromatography (30%ethyl acetate/hexane) to give ethyl2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetate.

EXAMPLE 17

The following compounds are prepared similarly to Example 16:

(a) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 133°-134° C., by coupling isobutylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(b)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclohexylmethyl)amino]acetamide,m.p. 145°-146° C., by coupling cyclohexanemethylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(c) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclohexyl)amino]acetamide,m.p. 148°-149° C., by coupling cyclohexylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(d) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](phenethyl)amino]acetamide,m.p. 137°-138° C., by coupling phenethylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(e)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-methylbutyl)amino]acetamide,m.p. 108° C., by coupling 1-amino-3-methylbutane with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(f) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](sec-butyl)amino]acetamide,m.p. 138° C., by coupling (sec)-butylamine with 4-methoxybenzenesulfonylchloride in the first step, and carrying out the subsequent steps asdescribed in example 16.

(g) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](tert-butyl)amino]acetamide,m.p. 150°-15 1° C., by coupling (tert)-butylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(h)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-fluorobenzyl)amino]acetamide,m.p. 115°-119° C., by coupling 4-fluorobenzylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(i)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-chlorobenzyl)amino]acetamide,m.p. 121°-123° C., by coupling 4-chlorobenzylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(j) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isopropyl)amino]acetamide,m.p. 139°-141° C., by coupling isopropylamine with4-methoxybenzenesulfonyl chloride in the fast step, and carrying out thesubsequent steps as described in example 16.

(k)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-methylbenzyl)amino]acetamide,m.p. 133°-135° C., by coupling 4-methylbenzylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(l)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-phenyl-1-propyl)amino]acetamideby coupling 3-phenyl-1-propylamine with 4-methoxybenzenesulfonylchloride in the first step, and carrying out the subsequent steps asdescribed in example 16.

(m)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-phenylbutyl)amino]acetamide,m.p. 109°-112° C., by coupling 4-phenylbutylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(n)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-cyclohexylethyl)amino]acetamide,m.p. 143°-144° C., by coupling 2-cyclohexylethylamine with4-methoxybenzenesulfonyl chloride in the fast step, and carrying out thesubsequent steps as described in example 16.

(o)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-phenylbenzyl)amino]acetamideby coupling 4-phenylbenzylamine with 4-methoxybenzenesulfonyl chloridein the fast step, and carrying out the subsequent steps as described inexample 16.

(p)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2,2,2-trifluoroethyl)amino]acetamide,m.p. 142°-143° C., by coupling 2,2,2-trifluoroethylamine with4-methoxybenzenesulfonyl chloride in the first step, and carrying outthe subsequent steps as described in example 16.

(q) N-Hydroxy-2-[[benzenesulfonyl](isobutyl)amino]acetamide, m.p.130°-131° C., by coupling isobutylamine with benzenesulfonyl chloride inthe first step, and carrying out the subsequent steps as described inexample 16.

(r)N-Hydroxy-2-[[4-trifluoromethylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 130°-131° C., by coupling isobutylamine with4-trifluoromethylbenzenesulfonyl chloride in the first step, andcarrying out the subsequent steps as described in example 16.

(s) N-Hydroxy-2-[[4-chlorobenzenesulfonyl](isobutyl)amino]acetamide,m.p. 126°-127° C., by coupling isobutylamine with4-chlorobenzenesulfonyl chloride in the first step, and carrying out thesubsequent steps as described in example 16.

(t) N-Hydroxy-2-[[4-methylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 138°-140° C., by coupling isobutylamine with4-methylbenzenesulfonyl chloride in the first step, and carrying out thesubsequent steps as described in example 16.

(u) N-Hydroxy-2-[[4-fluorobenzenesulfonyl](isobutyl)amino]acetamide,m.p. 144°-146° C., by coupling isobutylamine with4-fluorobenzenesulfonyl chloride in the first step, and carrying out thesubsequent steps as described in example 16.

(v) N-Hydroxy-2-[[2-thiophenesulfonyl](isobutyl)amino]acetamide bycoupling isobutylamine with 2-thiophenesulfonyl chloride in the firststep, and carrying out the subsequent steps as described in example 16.

(w) N-Hydroxy-2-[[benzenesulfonyl](benzyl)amino]acetamide, m.p. 90°-93°C., by coupling benzylamine with benzenesulfonyl chloride in the firststep, and carrying out the subsequent steps as described in example 16.

(x) N-Hydroxy-2-[[4-nitrobenzenesulfonyl](isobutyl)amino]acetamide, m.p.128°-130° C., by coupling isobutylamine with 4-nitrobenzenesulfonylchloride in the first step, and carrying out the subsequent steps asdescribed in example 16.

(y)N-Hydroxy-2-[[4-(tert)-butylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 113°-114° C., by coupling isobutylamine with4-(tert)-butylbenzenesulfonyl chloride in the first step, and carryingout the subsequent steps as described in example 16.

(z)N-Hydroxy-2-[[4-methylsulfonylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 159°-161° C., by coupling isobutylamine with4-methylsulfonylbenzenesulfonyl chloride in the first step, and carryingout the subsequent steps as described in example 16.

(aa)N-Hydroxy-2-[[3-trifluoromethylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 140°-141° C., by coupling isobutylamine with3-trifluoromethylbenzenesulfonyl chloride in the first step, andcarrying out the subsequent steps as described in example 16.

(bb)N-Hydroxy-2-[[2,4,6-trimethylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 142°-143° C., by coupling isobutylamine with2,4,6-trimethylbenzenesulfonyl chloride in the fast step, and carryingout the subsequent steps as described in example 16.

(cc)N-Hydroxy-2-[[2,5-dimethoxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 50°-53° C., by coupling isobutylamine with2,5-dimethoxybenzenesulfonyl chloride in the fast step, and carrying outthe subsequent steps as described in example 16.

(dd)N-Hydroxy-2-[[3,4-dimethoxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 146°-148° C., by coupling isobutylamine with3,4-dimethoxybenzenesulfonyl chloride in the fast step, and carrying outthe subsequent steps as described in example 16.

(ee)N-Hydroxy-2-[[2,4,6-triisopropylbenzenesulfonyl](isobutyl)amino]acetamide,m.p. 131°-133° C., by coupling isobutylamine with2,4,6-triisopropylbenzenesulfonyl chloride in the first step, andcarrying out the subsequent steps as described above.

(ff)N-Hydroxy-2-[[3,5-dimethylisoxazole-4-sulfonyl(benzyl)amino]acetamide,m.p. 140° C., by coupling benzylamine with3,5-dimethylisoxazole-4-sulfonyl chloride in the first step, andcarrying out the subsequent steps as described in example 16.

(gg)N-Hydroxy-2-[[2,4-dimethylthiazole-5-sulfonyl(benzyl)amino]acetamide,m.p. 55° C., by coupling benzylamine with2,4-dimethylthiazole-5-sulfonyl chloride in the first step, and carryingout the subsequent steps as described in example 16.

EXAMPLE 18

Ethyl 2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate (0.90g, 2.3 mmol) is dissolved in methanol (20 mL). To this solution is addedhydroxylamine hydrochloride (0.80 g, 11.5 mmol), followed by theaddition of sodium methoxide (5.2 mL of a 2.67M solution). The reactionis stirred overnight at room temperature. The reaction is worked up bypartitioning between dilute hydrochloric acid (pH=˜3) and ethyl acetate.The aqueous phase is extracted well with ethyl acetate, the combinedorganic layers are washed with brine, dried (Na₂ SO₄), and the solventis evaporated. The product is recrystallized from ether/ethyl acetate togiveN-hydroxy-2-[[4-methoxybenzenesulfonyl]-(4-methoxybenzyl)amino]acetamide,m.p. 134°-135.5° C.

The starting material is prepared as follows:

Glycine ethyl ester hydrochloride (31.39 g, 225.0 mmol) is dissolved indioxane (150 mL) and water (150 mL), triethylamine (69.0 mL, 495.0 mmol)is added, and the solution is cooled to 0° C. To this solution is added4-methoxybenzenesulfonyl chloride (51.15 g, 248.0 mmol) over 10 minutes.The reaction is warmed to room temperature and stirred overnight. Thenext day the mixture is reduced to one-half volume by evaporatingsolvent, diluted with 1N sodium hydroxide, and extracted well withether. The combined organic layers are washed with brine, dried (Na₂SO₄), and the solvent is evaporated. The product is recrystallized fromether/ethyl acetate/hexanes to give ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate.

To a suspension of sodium hydride (0.906 g, 22.67 mmol) indimethylformamide (50.0 mL), is added ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate (4.13 g, 15.11 mmol) and4-methoxybenzyl chloride (2.17 mL, 15.87 mmol), and the reaction isstirred overnight at room temperature. The reaction is cooled to 0° C.,quenched with 1N hydrochloric acid, and extracted well with ether. Thecombined organic layers are washed with brine, dried (Na₂ SO₄), and thesolvent is evaporated. The product is recrystallized from ether/hexanesto give ethyl2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate.

EXAMPLE 19

The following compounds are prepared similarly to example 18:

(a) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-picolyl)amino]acetamide,m.p. 138.5°-139.5° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate with 2-picolyl chloride inthe second step, and carrying out the other steps as described inexample 18.

(b) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl)amino]acetamide,m.p. 144°-145° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate with 3-picolyl chloride inthe second step, and carrying out the other steps as described inexample 18.

(c) N-Hydroxy-2-[[4-methoxybenzenesulfonyl](piperonyl)amino]acetamide,m.p. 143°-144° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate with piperonyl chloride inthe second step, and carrying out the other steps as described inexample 18.

(d)N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-piperidinylethyl)amino]acetamide,m.p. 120°-122° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate withN-(2-chloroethyl)-piperidine in the second step, and carrying out theother steps as described in example 18.

EXAMPLE 20

(a)N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide(1.15 g, 2.42 mmol) is dissolved in methylene chloride (30.0 mL) andethanol (0.20 mL) in a glass sealed tube. Hydrochloric acid gas (from alecture bottle) is bubbled through the solution for 20 minutes, and thenthe tube is sealed and stands at room temperature overnight. The nextday, additional hydrochloric acid gas is bubbled through the solutionfor 20 minutes, more ethanol (0.20 mL) is added, and then the tube issealed and stands at room temperature for two days. After that time, thesolvent is removed. The product is purified by silca gel chromatography(5% to 15% methanol/methylene chloride with ˜1% ammonium hydroxide) togiveN-hydroxy-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide,m.p. 177°-178° C.

The starting material is prepared as follows:

To a suspension of sodium hydride (0.84 g, 35.0 mmol) indimethylformamide (120.0 mL), is added ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate (3.19 g, 11.67 mmol) and 2-(chloromethyl)quinoline (2.62 g, 12.26 mmol), and the reaction isstirred for three days at room temperature. Then, additional NaH (0.46g, 11.67 mmol) is added, and the reaction is heated to 50° C. for 5hours. The reaction is cooled to 0° C., quenched with water, andextracted well with ether. The combined organic layers are washed withbrine, dried (Na₂ SO₄), and the solvent is removed to give ethyl2-[[4-methoxybenzenesulfonyl]-(2-quinolinylmethyl)amino]acetate.

Ethyl 2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetate(4.0 g, 9.63 mmol) is dissolved in tetrahydrofuran (70.0 mL). To thissolution is added lithium hydroxide (18.0 mL of a 1N aqueous solution,18.0 mmol), and the reaction is stirred at room temperature or might.The tetrahydrofuran is evaporated, the reaction is then acidified topH=˜3 using 1N hydrochloric acid, and extracted well with ethyl acetate.

The combined organic layers are dried (Na₂ SO₄), and the solvent isevaporated to give2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetic acidhydrochloride.

2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetic acidhydrochloride (1.49 g, 3.35 mmol), 1-hydroxybenzotriazole (0.539 g, 3.52mmol), 4-methylmorpholine (1.55 mL, 14.9 mmol), and O-t-butylhydroxylamine hydrochloride (0.464 g, 3.70 mmol) are dissolved in methylenechloride (50.0 mL),and the reaction is cooled to 0° C. To this solutionis added N- [dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride(1.35 g, 7.04 mmol), and the reaction is allowed to warm up to roomtemperature and stir overnight. The reaction is diluted with moremethylene chloride, and the organic layer is washed with saturatedsodium bicarbonate, brine, dried (MgSO₄), and the solvent is evaporated.The product is purified by silica gel chromatography (1%methanol/methylene chloride) to giveN-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide.

(b) Similarly prepared isN-hydroxy-2-[[4-methoxybenzenesulfonyl](4-picolyl)amino]-acetamidehydrochloride, m.p. 193° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]-amino]acetate with 4-picolyl chloride inthe second step, and carrying out the other steps as described above.

EXAMPLE 21

(a) 2-[[4-Methoxybenzenesulfonyl](6-chloropiperonyl)amino]acetic acid(1.87 g, 4.51 mmol) is dissolved in methylene chloride (45.0 mL). Tothis solution is added oxalyl chloride (0.784 mL, 9.02 mmol) anddimethylformamide (0.35 mL, 4.51 mmol), and the reaction is stirred atroom temperature for 60 minutes. Meanwhile, in a separate flask,hydroxylamine hydrochloride (1.25 g, 18.04 mmol) and triethylamine (3.77mL, 27.06 mmol) are stirred in tetrahydrofuran (20.0 mL) and water (5.0mL) at 0° C. for 15 minutes. After 60 minutes, the methylene chloridesolution is added in one portion to the second flask, and the combinedcontents are stirred overnight as the flask gradually warms up to roomtemperature. The reaction is then diluted with acidic water (pH=˜3), andextracted several times with ethyl acetate. The combined organic layersare dried (Na₂ SO₄), and the solvent is evaporated. The product isrecrystallized from ethyl acetate/methanol/acetone to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](6-chloropiperonyl)amino]acetamide,m.p. 168°-169° C.

The starting material is prepared as follows:

To a suspension of sodium hydride (1.08 g, 27.06 mmol) indimethylformamide (180.0 mL), is added ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate (4.93 g, 18.04 mmol) and6-chloropiperonyl chloride (3.88 g, 19.0 mmol), and the reaction isstirred overnight at room temperature. The reaction is cooled to 0° C.,quenched with 1N hydrochloric acid, and extracted well with ether. Thecombined organic layers are washed with brine, dried (Na₂ SO₄), and thesolvent is evaporated. The product is recrystallized from ether/hexanesto give ethyl2-[[4-methoxybenzenesulfonyl](6-chloropiperonyl)amino]acetate.

Ethyl 2-[[4-methoxybenzenesulfonyl](6-chloropiperonyl)amino]acetate(2.12 g, 4.79 mmol) is dissolved in tetrahydrofuran (40.0 mL). To thissolution is added lithium hydroxide (10.0 mL of a 1N aqueous solution,10.0 mmol), and the reaction is stirred at room temperature overnight.The tetrahydrofuran is evaporated, the reaction is then acidified topH=˜3 using 1N hydrochloric acid, and extracted well with ethyl acetate.The combined organic layers are dried (Na₂ SO₄), and the solvent isevaporated to give 2-[[4-methoxybenzenesulfonyl](6-chloropiperonyl)amino]acetic acid.

(b) Similarly prepared isN-hydroxy-2-[[4-methoxybenzenesulfonyl](3,4,5-trimethoxybenzyl)amino]acetamide,m.p. 116°-118° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]amino]acetate with 3,4,5-trimethoxybenzylchloride in the second step, and carrying out the other steps asdescribed above.

(c) Similarly prepared isN-hydroxy-2-[[4-methoxybenzenesulfonyl](3-methoxybenzyl)amino]acetamide,m.p. 118°-119° C., by alkylating ethyl2-[[4-methoxybenzenesulfonyl]-amino]acetate with 3-methoxybenzylchloride in the second step, and carrying out the other steps asdescribed above.

EXAMPLE 22

Ethyl 2-[[4-methoxybenzenesulfonyl](2-[4-morpholino]ethyl)amino]acetate(7.1 g, 18.4 mmol) is dissolved in ethanol (100 mL), followed by theaddition of sodium spheres (1.1 g). To this solution is addedhydroxylamine hydrochloride (2.47 g, 35.5 mmol). The reaction isrefluxed overnight. The reaction is worked up by removing most of thesolvent, and partitioning between saturated sodium bicarbonate and ethylacetate. The aqueous phase is extracted well with ethyl acetate, thecombined organic layers are washed with brine, dried (MgSO₄), and thesolvent is evaporated. The product is purified by silica gelchromatography (80% ethyl acetate/16% methanol/4% acetic acid). Thesolvent is removed to give the product containing residual acetic acid.The product is partitioned between ethyl acetate and water (pH=7.1), theorganic phase is dried (MgSO₄), and the solvent is concentrated and thentriturated with ether to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](2-[4-morpholino]ethyl)amino]acetamide,m.p. 108°-112° C.

The starting material is prepared as follows:

Ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate (13.7 g, 50.0 mmol) isdissolved in ethanol (500 mL), followed by the addition of sodiumspheres (2.5 g, 109.0 mmol). To this solution is addedN-(2-chloroethyl)morpholine hydrochloride (10.0 g, 53.7 mmol), thereaction is stirred at room temperature for 2 hours, and then refluxedfor 1.5 hours. The reaction is partitioned between ethyl acetate andbrine. The aqueous phase is extracted well with ethyl acetate, thecombined organic layers are dried (MgSO₄), and the solvent is evaporatedto give ethyl2-[[4-methoxybenzenesulfonyl](2-[4-morpholino]ethyl)amino]-acetate.

EXAMPLE 23

N-Hydroxy-2-[[4-aminobenzenesulfonyl](isobutyl)amino]acetamide, m.p.50°-55° C., is obtained by hydrogenation ofN-hydroxy-2-[[4-nitrobenzenesulfonyl]-(isobutyl)amino]acetamide (seeexample 17x), m.p. 128°-130°, using 10% palladium on carbon.

The starting material is prepared according to example 16 by couplingisobutylamine and 4-nitrobenzenesulfonyl chloride in the first stepthereof.

EXAMPLE 24

N-Hydroxy-2-[[4-dimethylaminobenzenesulfonyl](isobutyl)amino]-acetamide,m.p. 127°-129° C., is obtained by methylation ofN-hydroxy-2-[[4-aminobenzenesulfonyl](isobutyl)amino]acetamide using theprocedure from Synthesis p. 709, 1987.

EXAMPLE 25

Ethyl 2-[[4-hexyloxybenzenesulfonyl](isobutyl)amino]acetate (1.22 g,3.05 mmol) is dissolved in methanol (15 mL). To this solution is addedhydroxylamine hydrochloride (0.43 g, 6.11 mmol), followed by theaddition of sodium methoxide, freshly prepared from sodium (0.35 g, 15.3mmol) dissolved in methanol (5 mL). The reaction is stirred for 36 hoursat room temperature. The reaction is worked up by partitioning betweendilute hydrochloric acid (pH=˜3) and ethyl acetate. The aqueous phase isextracted well with ethyl acetate, the combined organic layers are dried(Na₂ SO₄), and the solvent is evaporated. The product is crystallizedfrom hexane/ethyl acetate and collected by filtration to giveN-hydroxy-2-[[4-hexyloxybenzenesulfonyl](isobutyl)-amino]acetamide, m.p.108°-110° C.

The starting material is prepared as follows:

A solution of ethanethiol (15 mL) and methylene chloride (15 mL) iscooled to 0° C. Aluminum trichlofide (9.62 g, 72.2 mmol) is added (thesolution turns green), and the reaction is warmed to room temperature.Ethyl 2-[[4-methoxybenzenesulfonyl](isobutyl)-amino]acetate (4.75 g,14.44 mmol) is added in methylene chloride (5 mL), and the reaction isstirred for 3.5 hours at room temperature. The reaction is then slowlyquenched with water, and the crude reaction is partitioned between waterand methylene chloride. The aqueous layer is extracted well withmethylene chloride, the combined organic layers are dried (Na₂ SO₄), andthe solvent is evaporated. The product is purified by silica gelchromatography (25% to 50% ethyl acetate/hexane) to give ethyl2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate.

Ethyl 2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate (1.0 g, 3.17mmol) is dissolved in dimethylformamide (16 mL). Cesium carbonate (1.03g, 3.17 mmol) is added, followed by 1-iodohexane (0.47 mL, 3.17 mmol),and the reaction is stirred overnight at room temperature. The reactionis then partitioned between water and ethyl acetate, the aqueous layeris extracted well with ethyl acetate, the combined organic layers aredried (Na₂ SO₄), and the solvent is evaporated. The product is purifiedby silica gel chromatography (10% ethyl acetate/hexane) to give ethyl2-[[4-hexyloxybenzenesulfonyl](isobutyl)amino]acetate.

EXAMPLE 26

The following compounds are prepared similarly to example 25:

(a) N-Hydroxy-2-[[4-ethoxybenzenesulfonyl](isobutyl)amino]acetamide,byusing ethyl iodide in the cesium carbonate alkylation step, and carryingout the subsequent steps as described in example 25.

(b) N-Hydroxy-2-[[4-butyloxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 125°-127° C., by using iodobutane in the cesium carbonatealkylation step, and carrying out the subsequent steps as described inexample 25.

(c)N-Hydroxy-2-[[4-(3-methyl)butyloxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 93°-96° C., by using 1-iodo-3-methylbutane in the cesium carbonatealkylation step, and carrying out the subsequent steps as described inexample 25.

(d) N-Hydroxy-2-[[4-heptyloxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 120°-123° C., by using 1-iodoheptane in the cesium carbonatealkylation step, and carrying out the subsequent steps as described inexample 25.

(e)N-Hydroxy-2-[[4-(cyclohexylmethoxy)benzenesulfonyl](isobutyl)amino]acetamide,m.p. 75°-80° C., by using cyclohexylmethyl bromide in the cesiumcarbonate alkylation step, and carrying out the subsequent steps asdescribed in example 25.

(f)N-Hydroxy-2-[[4-isopropyloxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 65°-66° C., by using isopropyl bromide in the cesium carbonatealkylation step, and carrying out the subsequent steps as described inexample 25.

(g)N-Hydroxy-2-[[4-ethoxyethoxybenzenesulfonyl](isobutyl)amino]acetamide,m.p. 111°-114° C., by using 2-bromoethyl ethyl ether in the cesiumcarbonate alkylation step, and carrying out the subsequent steps asdescribed in example 25.

EXAMPLE 27

(a)N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide(0.77 g, 1.55 mmol) is dissolved in methylene chloride (2.0 mL) andethanol (0.1 mL) in a glass sealed tube, and the reaction is cooled to0° C. Hydrochloric acid gas (from a lecture bottle) is bubbled throughthe solution for 20 minutes, and then the tube is sealed at roomtemperature for 3 days. After that time, the solvent is removed, and thereaction is partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic phase is dried (Na₂ SO₄), and the solvent isevaporated. The product is purified by silica gel chromatography (2%methanol/methylene chloride) to giveN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide,m.p. 72°-75° C.

The starting material is prepared as follows:

D-asparagine (13.2 g, 100.0 mmol) is dissolved in dioxane (75.0 mL) andwater (125.0 mL), triethylamine (21.0 mL, 150.0 mmol) is added, and thesolution is cooled to 0° C. To this solution is added4-methoxybenzenesulfonyl chloride (22.7 g, 110.0 mmol) over 10 minutes.The reaction is warmed to room temperature and stirred for 3 days. Theprecipitate is then filtered off, the filtrate is acidified to pH=˜4,and extracted well with ethyl acetate. A first crop of pure productprecipitates from the ethyl acetate and is collected by filtration. Asecond crop is obtained by evaporating off the ethyl acetate, andrinsing the solid obtained with water to remove inorganic salts. The twocrops are combined to give N-[4-methoxybenzenesulfonyl]-(D)-asparagine.

N-[4-methoxybenzenesulfonyl]-(D)-asparagine (10.1 g, 33.3 mmol) isdissolved in dimethylformamide (167.0 mL). Cesium carbonate (5.43 g,16.66 mmol) is added, followed by the addition of methyl iodide (2.22mL, 33.3 mmol), and the reaction is stirred overnight. The reaction isthen diluted with saturated ammonium chloride (366.0 mL), and extractedwell with ethyl acetate. The combined organic extracts are washed withbrine, dried (Na₂ SO₄), and the solvent is evaporated. The crude productis recrystallized from toluene to provideN-[4-methoxybenzenesulfonyl]-(D)-asparagine methyl ester.

To a suspension of N-[4-methoxybenzenesulfonyl]-(D)-asparagine methylester (8.54 g, 27.0 mmol) in methylene chloride (47.0 mL) is addedpyridine (10.9 mL, 135.0 mmol). Para-toluenesulfonyl chloride (10.3 g,54.0 mmol) is added, and the reaction mixture is allowed to standwithout stirring at room temperature overnight. The next day, saturatedsodium bicarbonate is added (125.0 mL), and the mixture is stirred for 1hour. The mixture is then diluted with water and extracted well withethyl acetate. The combined organic extracts are washed with brine,dried (Na₂ SO₄), and the solvent is evaporated. The crude product isrecrystallized from 20% tetrahydrofuran/methanol to provide methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-4-cyano-propionate.

To a suspension of sodium hydride (0.93 g, 23.2 mmol) indimethylformamide (95.0 mL), is added methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-4-cyano-propionate (6.92 g, 23.2mmol) in dimethylformamide (10.0 mL). After stirring at room temperaturefor 20 minutes, benzyl bromide (3.1 mL, 25.5 mmol) is added, and thereaction is stirred overnight at room temperature. The reaction is thenpartitioned between ethyl acetate and acidic water (pH=˜5), the organiclayer is dried (Na₂ SO₄), and the solvent is evaporated. The product ispurified by silica gel chromatography (40% ethyl acetate/hexane) to givemethyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-cyano-propionate.

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-cyanopropionate (1.34g, 3.47 mmol) in dimethylformamide (5.4 mL) is added triethylaminehydrochloride (0.95 g. 6.93 mmol) and sodium azide (0.45 g, 6.93 mmol).The reaction is stirred at 110° C. overnight. The next day, the solventis evaporated, the residue is acidified with 1N hydrochloric acid (16.0mL), and extracted well with ethyl acetate. The combined organicextracts are washed with brine, dried (Na₂ SO₄), and the solvent isevaporated to yield methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(5-tetrazolyl)methyl]acetate.

This crude tetrazole is dissolved in dimethylformamide (17.4 mL). Cesiumcarbonate (0.56 g, 1.73 mmol) is added, followed by the addition ofmethyl iodide (0.23 mL, 3.47 mmol), and the reaction is stirredovernight. The reaction is then diluted with brine and extracted wellwith ethyl acetate. The combined organic extracts are washed with brine,dried (Na₂ SO₄), and the solvent is evaporated. The product is purifiedby silica gel chromatography (40% ethyl acetate/hexane) to giveseparately the two regioisomers: methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(1-methyl-5-tetrazolyl)methyl]acetate(0.50 g); and methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetate.

Methyl2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)-methyl]acetate(1.0 g, 2.27 mmol) is dissolved in tetrahydrofuran (11.3 mL) and water(11.3 mL). To this solution is added lithium hydroxide hydrate (0.095 g,2.27 mmol), and the reaction is stirred at room temperature for 2 hours.The reaction is then acidified to pH=˜3 using 1N hydrochloric acid, andextracted well with ethyl acetate. The combined organic extracts arewashed with brine, dried (Na₂ SO₄), and the solvent is evaporated toprovide2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)-methyl]aceticacid (0.96 g).

2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]aceticacid (0.96 g, 2.24 mmol), 1-hydroxybenzotriazole (0.30 g, 2.24 mmol),4-methylmorpholine (0.86 mL, 7.89 mmol), and O-t-butylhydroxylaminehydrochloride (0.30 g, 2.24 mmol) are dissolved in methylene chloride(75.0 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride(0.86 g, 4.48 mmol) is added, and the reaction is stirred overnight. Thereaction is then diluted with water and extracted with methylenechloride. The combined organic extracts are washed with brine, dried(Na₂ SO₄), and the solvent is evaporated. The crude product is purifiedby silica gel chromatography (50% ethyl acetate/hexane) to giveN-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide.

(b) Similarly prepared is the other tetrazole regioisomer,N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(1-methyl-5-tetrazolyl)methyl]acetamide,m.p. 92°-96° C., by completing the synthesis as described above.

(c) Similarly prepared isN-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(5-tetrazolyl)methyl]acetamide,m.p. 91°-94° C., by completing the synthesis as described above, excepttrityl chloride is used to protect the tetrazole ring in place of methyliodide.

(d) Similarly prepared isN-hydroxy-2-[[4-methoxybenzenesulfonyl](4-phenylbenzyl)-amino]-2-[(5-tetrazolyl)methyl]acetamide,m.p. 184° C., by completing the synthesis as described above, except4-chloromethylbiphenyl is used in place of benzyl bromide in thealkylation step.

EXAMPLE 28

Oxalyl chloride (106 mL, 1.22 mol) is added over 1 hour todimethylformamide (92 mL) in methylene chloride (1250 mL) at 0° C. Tothis is added a solution of2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acidhydrochloride (248 g, 0.6 mol) in dimethylformamide (450 mL) over 1hour, maintaining the temperature at 0° C. This solution is stirred anadditional 2 hours at room temperature, and then added dropwise to amixture of hydroxylamine (460 g of a 50% aqueous solution, 6.82 mol) intetrahydrofuran (2400 mL). The reaction is stirred an additional 3 hoursat 5° C., and then at room temperature overnight. The reaction mixtureis filtered, the organic layer is collected, and the solvent isevaporated. The crude product is re-dissolved in methylene chloride (2L), washed with water (2×1 L), saturated sodium bicarbonate (4×1 L),brine (1 L), dried (Na₂ SO₄), and the solvent is evaporated. The productis dissolved in ethyl acetate (700 mL) and diluted with ether (1400 mL)to induce precipitation. The pure product is collected by filtration toprovideN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide.After conversion to the hydrochloride salt, a white solid is obtained,m.p. 169°-170° C. (dec).

The starting material is prepared as follows:

To a solution of D-valine (2000 g, 17.09 mol) in water (16.9 L) andacetone (9.5 L), cooled to 5° C., is added triethylamine (4769 mL, 34.22mol), and the reaction is stirred for 30 minutes. Then a solution of4-methoxybenzenesulfonyl chloride (3524 g, 18.48 mol) in acetone (7.4 L)is added over 30 minutes, and the reaction is stirred at roomtemperature overnight. Most of the acetone is evaporated off, and the pHis adjusted to pH=8.25 with 6N sodium hydroxide. The crude product iswashed with toluene (2×10 L), and then the pH is re-adjusted to pH=2.2with 6N hydrochloric acid. The mixture is then extracted with methylenechloride (3×12 L), the combined organic layers are washed with 2Nhydrochloric acid, water, dried (Na₂ SO₄), and the solvent is evaporatedto provide N-[4-methoxybenzenesulfonyl]-(D)-valine.

To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine (8369 g, 29.13mol) in methanol (30 L) at 5° C. is added thionyl chloride (2176 mL,29.7 mol) over 2.5 hours. After stirring for 3 hours at 5° C., thereaction is stirred for 36 hours at room temperature. Most of thesolvent is evaporated, and the crude product is dissolved in toluene (80L). The toluene layer is then washed with water (20 L), saturated sodiumbicarbonate (20 L), water again (20 L), 2N hydrochloric acid (20 L),brine (20 L), dried (Na₂ SO₄), and the solvent is evaporated. The solidobtained is dissolved in ethyl acetate (8 L) and heptane (16 L) is addedto induce crystallization. The precipitated product is collected byfiltration to provide methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate.

To a solution of methyl2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate (1662 g, 5.52mol) in dimethylformamide (10.9 L) is added 3-picolyl chloridehydrochloride (947.3 g, 5.77 mol) followed by powdered potassiumcarbonate (2409.9 g, 17.36 mol). The reaction mixture is stirred at roomtemperature for 2 days. At that time, additional quantities of 3-picolylchloride hydrochloride (95 g) and powdered potassium carbonate (241 g)are added, and the reaction is stirred for 3 more days. The solids arethen filtered away, the crude product is poured into water (22 L), andthe pH is adjusted to pH=8 with 6N sodium hydroxide. This solution isextracted well with toluene (4×10 L), the combined organic layers arewashed with water (2×12 L), and then with 6N hydrochloric acid (3×1600mL). This aqueous layer is then re-adjusted to pH=8 with 6N sodiumhydroxide, extracted with toluene (4×10 L), dried (Na₂ SO₄), and thesolvent is evaporated. The oil obtained is re-dissolved in ethyl acetate(12 L), cooled to 5° C., and to this is added methanolic HCl (834 mL).After stirring for 2 hours, the precipitated product is collected byfiltration to give methyl2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-3-methylbutanoatehydrochloride.

Methyl2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoatehydrochloride (7164 g, 16.7 mol) is added to a solution of water (27 L)and concentrated hydrochloric acid (9 L), and heated to 120° C. for 3days. After cooling down to room temperature, charcoal (350 g) is added,stirring is continued for 45 minutes, the reaction is filtered, and thesolvent is evaporated. The crude solid is re-dissolved in methanol (7.1L) and ethyl acetate (73 L), and cooled to 3° C. for 2 hours. Theprecipitated product is collected by filtration to give2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acidhydrochloride.

EXAMPLE 29

N-Benzyloxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide(see example 29a) is reacted with hydrogen in the presence of 10%palladium on charcoal catalyst at room temperature and atmosphericpressure to yieldN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide.After conversion to the hydrochloride salt, a white solid is obtained,m.p. 169°-170° C. (dec).

(a) The N-(benzyloxy) substituted prodrug derivative of the abovecompound is prepared as follows:

2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acidhydrochloride is reacted with O-benzylhydroxylamine hydrochloride underconditions described for reaction with O-t-butylhydroxylaminehydrochloride to yieldN-(benzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanamide,m.p. 74.5°-76° C.

(b) The corresponding N-(4-methoxybenzyloxy) substituted prodrugderivative,N-(4-methoxybenzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanamide,is prepared as follows:

2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acidhydrochloride (2.41 g, 5.82 mmol), 1-hydroxybenzotriazole (0.786 g, 5.82mmol), 4-methyl-morpholine (1.9 mL, 17.46 mmol), andO-(4-methoxybenzyl)hydroxylamine (1.78 g, 11.63 mmol) (preparedaccording to Pol. J. Chem. 55, 1163°-1167 (1981 )) are dissolved inmethylene chloride (55 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimidehydrochloride (1.45 g, 7.57 mmol) is added, and the reaction is stirredovernight. The reaction is then diluted with water and extracted withmethylene chloride. The combined organic extracts are washed with brine,dried (Na₂ SO₄), and the solvent is evaporated. The crude product ispurified by silica gel chromatography (ethyl acetate followed by 5%methanol/ethyl acetate) to giveN-(4-methoxybenzyloxy)-2CR)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide,m.p. 45°-53° C.

Similarly prepared are: (c) the N-(2,4-dimethoxybenzyloxy)-substitutedprodrug derivative,N-(2,4-dimethoxybenzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-3-methyl-butanamide,m.p. 45°-60° C.;

(d) the N-(2-methoxybenzyloxy)-substituted prodrug derivative,N-(2-methoxybenzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanamide,m.p. 46°-56° C.

EXAMPLE 30

N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3(R)-(3-picolyloxy)butanamide(1.3 g, 2.4 mmol) is dissolved in methylene chloride (50 mL) containingethanol (0.14 mL, 2.4 mmol) in a round bottom flask, and the reaction iscooled to -10° C. Hydrochloric acid gas (from a lecture bottle) isbubbled through for 20 minutes. The reaction is sealed, allowed toslowly warm to room temperature, and stirred for two days. The solventis reduced to 1/3 the volume by evaporation and the residue istriturated with ether. The mixture is filtered, the fiter cake isremoved and dried in vacuo to provideN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3(R)-(3-picolyloxy)-butanamidedihydrochloride as a white solid; [α]_(D) ²⁵ =+35.26° (c=5.58, DMSO).

The starting material is prepared as follows:

To a solution of D-threonine (5.0 g, 0.042 mol) in water (50 mL) anddioxane (50 mL) containing triethylamine (8.9 mL, 0.063 mol) at roomtemperature is added 4-methoxybenzenesulfonyl chloride (9.54 g, 0.046mol). The reaction mixture is stirred overnight at room temperature.Most of the dioxane is evaporated off, and the pH is adjusted to pH=2with 1N HCl. The mixture is then extracted with ethyl acetate. Thecombined organic extracts are washed with brine, dried (Na₂ SO₄), andconcentrated in vacuo to provideN-[4-methoxybenzenesulfonyl]-(D)-threonine.

N-[4-methoxybenzenesulfonyl]-(D)-threonine (4.0 g, 13.84 mmol),1-hydroxybenzotriazole (1.87 g, 13.84 mmol), 4-methylmorpholine (7.9 mL,69.2 mmol), and O-t-butylhydroxylamine hydrochloride (5.22 g, 41.52mmol) are dissolved in methylene chloride (100 mL). To this solution isadded N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.45g, 17.99 mmol), and the reaction is stirred overnight. The mixture isthen diluted with water and extracted with methylene chloride. Thecombined organic extracts are washed with brine, dried (Na₂ SO₄), andconcentrated in vacuo. The crude product is purified by silica gelchromatography (ethyl acetate) to giveN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-amino]-3(R)-hydroxybutanamide.

To a solution ofN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]amino]-3(R)-hydroxybutanamide(3.04 g, 8.44 mmol) in dimethylformamide (150 mL) is added 3-picolylchloride hydrochloride (1.45 g, 8.87 mmol) followed by potassiumcarbonate (11.65 g, 84.4 mmol). The reaction mixture is stirred at roomtemperature overnight, then heated to 45° C. for 5 hours. An additionalamount of 3-picolyl chloride hydrochloride (692.0 mg, 4.23 mmol) isadded at this point. The reaction mixture is stirred at 45° C. for 10hours. The reaction mixture is diluted with water and extracted withethyl acetate. The combined organic extracts were washed with brine,dried (Na₂ SO₄), and concentrated in vacuo. The crude product ispurified by silica gel chromatography (ethyl acetate, then 5%methanol/methylene chloride) to giveN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3(R)-(3-picolyloxy)butanamide.

EXAMPLE 31

(a)N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](4-picolyl)amino]-cyclohexylacetamide(1.9 g, 3.9 mmol) is dissolved in dichloroethane (50 mL) containingethanol (0.21 ml, 3.9 mmol) in a round bottom flask, and the reaction iscooled to -10° C. Hydrochloric acid gas (from a lecture bottle) isbubbled through for 30 minutes. The reaction is sealed, allowed toslowly warm to room temperature, and stirred for 4 days. The solvent isreduced to 1/3 volume by evaporation and triturated with ether. Themixture is filtered, filter cake removed, and dried in vacuo to provideN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](4-picolyl)amino]-2-cyclohexylacetamidehydrochloride as a white solid, m.p. 154.5°-156° C.

The starting material is prepared as follows:

To a solution of D-cyclohexylglycine hydrochloride (10.4 g, 53.7 mmol)in 1:1 dioxane/water (200 mL) containing triethylamine (37.0 g, 366.0mmol) at room temperature is added 4-methoxybenzenesulfonyl chloride(15.0 g, 73.0 mmol), and the reaction mixture is stirred at roomtemperature overnight. The mixture is then diluted with methylenechloride, washed with 1N aqueous hydrochloric acid and water. Theorganic layer is washed again with brine, dried (Na₂ SO₄), and thesolvent is evaporated to provideN-[4-methoxybenzenesulfonyl]-(D)-cyclohexylglycine as a crude product. Asolution of this crude product in toluene (200 mL) containingN,N-dimethylformamide di-t-butyl acetal (48.5 mL, 200.0 mmol) is heatedto 95° C. for 3 hours. The solvent is then evaporated. The crude productis purified by silica gel chromatography (30% ethyl acetate/hexanes) toprovide N-[4-methoxybenzenesulfonyl](D)-cyclohexylglycine t-butyl ester.

To a solution of N-[4-methoxybenzenesulfonyl]-(D)-cyclohexylglycinet-butyl ester (2.0 g, 4.1 mmol) in dimethylformamide (100 mL) is added4-picolyl chloride hydrochloride (0.74 g, 4.5 mmol) followed bypotassium carbonate (5.61 g, 40.7 mmol). The reaction mixture is stirredat room temperature for 4 days. The mixture is then diluted with waterand extracted with ethyl acetate. The combined organic extracts arewashed with brine, dried (Na₂ SO₄), and the solvent is evaporated. Thecrude product is purified by silica gel chromatography (ethyl acetate)to give t-butyl2(R)-[[4-methoxybenzenesulfonyl]-(4-picolyl)amino]-2-cyclohexylacetate.

t-Butyl2(R)-[[4-methoxybenzenesulfonyl](4-picolyl)amino]-cyclohexylacetate (2.0g, 4.2 mmol) is dissolved in methylene chloride (80 mL) and cooled to-10° C. Hydrochloric acid gas is bubbled into the solution for 10minutes. The reaction mixture is then sealed, warmed to room temperatureand stirred overnight. The solvent is then evaporated to provide2(R)-[[4-methoxybenzenesulfonyl](4-picolyl)amino]-2-cyclohexylaceticacid hydrochloride.

2(R)-[[4-Methoxybenzenesulfonyl](4-picolyl)amino]-cyclohexylacetic acidhydrochloride (1.8 g, 4.2 mmol), 1-hydroxybenzotriazole (0.65 g, 4.81mmol), 4-methyl-morpholine (2.4 mL, 24.04 mmol), andO-t-butylhydroxylamine hydrochloride (1.81 g, 14.4 mmol) are dissolvedin methylene chloride (100 mL).N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.2 g, 6.25mmol) is added, and the reaction is stirred overnight. The reaction isthen diluted with water and extracted with methylene chloride. Thecombined organic extracts are washed with brine, dried (Na₂ SO₄), andthe solvent is evaporated. The crude product is purified by silica gelchromatography (5% methanol/methylene chloride) to giveN-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(4-picolyl)amino]-2-cyclohexylacetamide.

(b) Similarly prepared isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](2-(2-pyridyl)ethyl)amino]-2-cyclohexylacetamide,m.p. 131.5°-134.0° C.

The first two steps are carded out as described above. A Mitsunobu stepis substituted for the alkylation step as described below.

To a stirring solution ofN-[4-methoxybenzenesulfonyl]-(D)-cyclohexylglycine-t-butyl ester (2.0 g,5.25 mmol) in tetrahydrofuran (50 mL) is added triphenylphosphine (4.13g, 15.75 mmol) and 2-(2-hydroxyethyl)-pyridine (646.0 mg, 5.25 mmol)followed by diethyl azodicarboxylate (2.28 g, 13.1 mmol). The reactionmixture is stirred at room temperature for 48 hours. The mixture isconcentrated directly in vacuo. The crude mixture is applied to a columnof silica gel (30% ethylacetate/hexane) to provide t-butyl2(R)-[N-[4-methoxybenzenesulfonyl](2-(2-pyridyl)othyl)amino]-2-cyclohexylacetate.

All of the subsequent steps are carried out as described under (a).

(c) Similarly prepared isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-(3-pyridyl)propyl)amino]-2-cyclohexylacetamide,m.p. 136.0°-138° C., by using 3-pyridinepropanol in the Mitsunobu step,and carrying out the subsequent steps as described above.

(d) Similarly prepared isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](2-methylpyrid-5-ylmethyl)amino]-2-cyclohexylacetamide,m.p. 156.5°-157.0° C., by using 6-methyl-3-pyridinemethanol (prepared asin J. Org. Chem. 53, 3513 (1988)) in the Mitsunobu step, and carryingout the subsequent steps as described above.

(e) Similarly prepared isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](4-tetrahydropyranmethyl)amino]-2-cyclohexylacetamide,m.p. 75.0°-87.0° C., by using 4-(hydroxymethyl)tetrahydropyran (preparedas in Okrytiya. Izobret. 82 (1985)) in the Mitsunoba step, and carryingout the subsequent steps as described above.

EXAMPLE 32

(a)N-(t-Butyloxy)-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(4-N-methylpiperidinyl)acetamide(733.0 mg, 1.46 mmol) is dissolved in methylene chloride (60 mL)containing ethanol (67.0 mg, 146 mmol), and the reaction is cooled to-10° C. Hydrochloric acid gas (from a lecture bottle) is bubbled throughfor 15 minutes. The reaction is sealed, allowed to slowly warm to roomtemperature, and stirred for 6 days. The solvent is reduced to 1/3volume by evaporation and triturated with ether. The mixture isfiltered, filter cake removed, and dried in vacuo to provideN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(4-N-methylpiperdinyl)acetamidehydrochloride as a light tan solid, m.p. >160° C. (dec).

The starting material is prepared as follows:

To a solution of ethyl 4-pyridylacetate (11.17 g, 67.62 mmol) in 2Nhydrochloric acid (100 mL) is added platinum (IV) oxide (275 mg). Themixture is shaken in a Parr hydrogenation apparatus for 60 hours under ahydrogen pressure of 50 psi (=3.45 bar). The reaction mixture isbasified to pH 8-9 with saturated aqueous sodium carbonate and thenwashed with methylene chloride. The aqueous layer is concentrated invacuo providing sodium 4-piperidyl acetate as a white solid. To asolution of the crude product (5.0 g, 30.3 mmol) in 3:1 water/dioxane(200 mL) at 0° C. is added a solution of di-tert-butyldicarbonate (6.38g, 29.3 mmol) in dioxane (25 mL) in one portion. The cloudy reactionmixture is warmed to room temperature and stirred overnight. The mixtureis then filtered, cooled to 0° C. and acidified with cold 6Nhydrochloric acid (pH=2-3).This solution is extracted with ethylacetate. The combined organic layers are dried (Na₂ SO4), and thesolvent is evaporated to provide N-t-BOC-piperidine-4-acetic acid as awhite crystalline solid.

To a solution of N-t-BOC-piperidine-4-acetic acid (4.67 g, 19.22 mmol)in tetrahydrofuran at -78° C. is added triethylamine (2.53 g, 24.99mmol) followed by pivaloyl chloride (2.55 g, 21.14 mmol). The resultingwhite slurry is stirred at -78° C. for 15 minutes, warmed to 0° C. for45 minutes, then recooled to -78° C. In a separate flask,(R)-(+)-4-benzyl-2-oxazolidinone (4.09 g, 23.1 mmol) is dissolved intetrahydrofuran (50 mL) and 1M n-butyl lithium in hexanes (14.4 mL,23.06 mmol) is added dropwise at -78° C. The solution is added viacannula to the aforementioned white slurry at -78° C. The reactionmixture is stirred at -78° C. for 15 minutes, then warmed to roomtemperature over 2.5 hours. The mixture is quenched with saturatedaqueous sodium carbonate and the tetrahydrofuran is evaporated in vacuo.The remaining aqueous layer is diluted with water and extracted withethyl acetate. The combined organic extracts are washed with brine,dried (Na₂ SO₄), and the solvent is evaporated under vacuum. The productis purified by silica gel chromatography (75% to 50% hexane/ethylacetate) to give3-[2-(N-t-BOC-4-piperidinyl)-1-oxoethyl]-4(R)-(benzyl)-2-oxazolidinone.

To a solution of3-[2-(N-t-BOC-4-piperidinyl)-l-oxoethyl]-4(R)-(benzyl)-2-oxazolidinone(7.54 g, 18.76 mmol) in tetrahydrofuran (175 mL) at -78° C. is added a0.5M solution of potassium bis (trimethylsilylamide in toluene (37.5 mL,18.76 mmol) dropwise. After stirring for 20 minutes at -78° C., apre-cooled solution of trisylazide (7.25 g, 23.4 mmol) intetrahydrofuran (55 mL) is added via cannula at -78° C. The mixture isstirred for 15 minutes at -78° C., then acetic acid 3.38 g, 56.28 mmol)is added followed by immediate warming to room temperature throughimmersion in a water bath. The reaction mixture is stirred for 1.5 hoursat room temperature. The tetrahydrofuran is removed under vacuum and theresulting residue is partitioned between saturated aqueous sodiumcarbonate and ethyl acetate. The aqueous layer is removed and extractedwith ethyl acetate. The combined organic extracts are washed with brine,dried (Na₂ SO₄), and concentrated in vacuo. The product is purified bysilica gel chromatography (30% to 50% ethyl acetate/hexanes) to give3-[2-(R)-azido-2-(N-t-BOC-4-piperidinyl)-1-oxoethyl]-4(R)-(benzyl)-2-oxazolidinone.

To a solution of3-[2-(R)-azido-2-(N-BOC-4-piperidinyl)-1-oxoethyl]-4(R)-(benzyl)-2-oxazolidinone(5.84 g, 13.17 mmol) in 3:1 tetrahydrofuran/water/200 mL) at 0° C. isadded 30% aqueous hydrogen peroxide (5.12 mL, 52.67 mmol) followed bylithium hydroxide monohydrate (1.11 g, 26.34 mmol). The reaction mixtureis stirred at 0° C. for 1 hour. The mixture is quenched by addition ofsodium sulfite (7.1 g) at 0° C. The tetrahydrofuran is removed in vacuoand the remaining aqueous layer is further diluted with water. Thisaqueous layer is then washed with methylene chloride and acidified with1N hydrochloric acid. The resulting acidic aqueous layer is extractedwith ethyl acetate. The combined organic extracts are dried (Na₂ SO₄)and concentrated in vacuo to provide crude2-(R)-azido-2-(N-t-BOC-4-piperidinyl)acetic acid.

To a pre-stirred solution of tin (II) chloride (3.14 g, 16.55 mmol) inmethanol (100 mL) at 0° C. is added2-(R)-azido-2-(N-t-BOC-4-piperidinyl)acetic acid (2.35 g, 8.27 mmol) inmethanol (25 mL) dropwise. The reaction mixture is stirred at 0° C. for10 minutes then warmed to room temperature overnight. The methanol isremoved in vacuo to provide crude R-(N-t-BOC-4-piperidinyl) glycine,which is used directly in the next reaction without purification. Thecrude product from the above reaction is dissolved in 2:1 dioxane/water(120 mL) and triethylamine (7.53 g, 74.43 mmol) and cooled to 0° C. Tothis mixture is added 4-methoxybenzenesulfonyl chloride (2.22 g, 10.75mmol) and then the reaction mixture is warmed to room temperatureovernight. The dioxane is removed in vacuo and the residue ispartitioned between dilute aqueous sodium bicarbonate and ethyl acetate.The basic aqueous layer is removed, acidified with 1N hydrochloric acid,and extracted with ethyl acetate. The resulting emulsion is passedthrough a celite pad washing with ethyl acetate. The organic filtrate isdried (Na₂ SO₄) and concentrated in vacuo to provide2(R)-[(4-methoxybenzenesulfonyl)amino]-2-(N-t-BOC-4-piperidinyl) aceticacid as crude product.

A solution of crude2(R)-[(4-methoxybenzenesulfonyl)amino]-2-(N-t-BOC-4-piperidin-yl)-aceticacid (2.88 g) in dimethylformamide (60 mL) containingN,N-dicyclohexylamine (1.22 g, 6.73 mmol) and benzyl bromide (1.15 g,6.73 mmol) is stirred at room temperature for 3.5 hours. To this samereaction mixture is again added benzyl bromide (1.26 g, 7.4 mmol)followed by potassium carbonate (6.5 g, 47.11 mmol). The reactionmixture is stirred over the weekend at room temperature. The mixture isdiluted with water and extracted with ethylacetate. The combined organicextracts are washed with brine, dried (Na₂ SO₄), and concentrated invacuo. The crude product is purified by silica gel chromatography (15%to 25% ethyl acetate/hexanes) to provide benzyl2(R)-[(4-methoxybenzenesulfonyl)(benzyl)-amino]-2-(N-t-BOC-4-piperidinyl)acetate.

A solution of benzyl2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(N-t-BOC-4-piperidinyl)acetate (2.0 g, 3.3 mmol) in dichloromethane (50 mL) is cooled to 0° C.and hydrochloric acid gas (from a lecture bottle) is bubbled through for10 minutes. The reaction mixture is warmed to room temperature over 30minutes. The solvent is removed in vacuo to yield benzyl2(R)-[(4-methoxybenzenesulfonyl)(benzyl)-amino]-2-(N-t-BOC-4-piperidinyl)acetate hydrochloride as a white foam.

To a solution of benzyl 2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(N-t-BOC-4-piperidinyl) acetate hydrochloridesalt (1.28 g, 2.35 mmol) heated to reflux is added sodium formate (480.0me, 7.06 mmol) and formaldehyde (0.57 mL, 7.06 mmol). The reactionmixture is refluxed for 10 minutes, then two additional aliquots offormaldehyde (0.57 mL, 7.06 mmol) are added at 10 minute intervals. Thereaction mixture is refluxed for an additional 3 hours. The formic acidis removed in vacuo and the residue is partioned between saturatedaqueous sodium bicarbonate and ethyl acetate. The basic aqueous layer isfurther extracted with ethyl acetate. The combined organic extracts arewashed with brine, dried (Na₂ SO₄) and concentrated in vacuo to providebenzyl2(R)-[(4-methoxybenzenesulfonyl)benzyl)amino]-2-(4-N-methylpiperidinyl)acetate as a crude product. A solution of this crude product (1.23 g) in3N HCl (40 mL) is refluxed at 120° C. for 2 days. The mixture isconcentrated in vacuo to provide acid as a crude product. To a solutionof this crude product (1.08 g) in methylene chloride (75 mL) is added1-hydroxybenzotriazole (0.312 g, 2.31 mmol), 4-methylmorpholine (1.64 g,16.17 mmol), O-t-butylhydroxylamine hydrochloride (870.0 mg, 6.93 mmol),followed by N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride(576.0 mg, 3.0 mmol). The reaction mixture is stirred at roomtemperature overnight. The reaction is then diluted with water andextracted with methylene chloride. The combined organic extracts arewashed with brine, dried (Na₂ SO₄), and the solvent is evaporated. Thecrude product is purified by silica gel chromatography (3% to 7%methanol/methylene chloride containing 0.5% ammonium hydroxide) to giveN-(t-butyloxy)-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)-amino]-2-(4-N-methylpiperidinyl)acetamide.

(b) Similarly prepared isN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-[N-(dimethylaminoacetyl)-4-piperidinyl]acetamide,m.p. 130°-150° C.;

The required intermediate is prepared as follows:

To benzyl2-(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(4-piperidinyl)acetate(0.866 g, example 32(a)) in methylene chloride (50 ml) is addedN,N-dimethylglycine (0.172 g), N-methylmorpholine (0.7 ml),1-hydroxybenzotriazole (0.215 g) and1-(3-di-methylaminopropyl)-3-ethylcarbodiimide (0.610 g). The mixture isstirred at room temperature over the weekend, diluted with water andextracted with methylene chloride. The combined organic extracts aredried over Na₂ SO₄ and evaporated to dryness to yield benzyl2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2[(N-dimethylaminoacetyl)-4-piperidinyl]acetate.

(c) Similarly prepared isN-hydroxy-2-(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(3-pyrrolidinyl)-acetamidehydrochloride, m.p. 160° C. dec.

(d) Similarly prepared isN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(N-t-butoxycarbonyl-3-pyrrolidinyl)-acetamide,m.p. 120° C. dec., starting with N-t-butoxycarbonyl-3-pyrrolidineaceticacid.

(e) Similarly prepared isN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)-amino]-2-(4-tetrahydropyranyl)-acetamidehydrochloride, m.p. >152° C. dec. starting withtetrahydropyranyl-4-acetic acid.

EXAMPLE 33

Prepared similarly to the previous examples isN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(3-picolyl)amino]-2(trans4-hydroxycyclohexyl)-acetamide hydrochloride, m.p. 130°-155° C.

The starting material is prepared as follows:

D-4-hydroxyphenylglycine (10 g) is dissolved in 3N sodium hydroxide (20ml). Water (180 ml) and then Raney nickel (27 g) are added. The reactionmixture is hydrogenated at about 3 atmospheric pressure and 50°-80° C.overnight.

The reaction mixture is filtered and reduced in volume to about 85 mland dioxane (85 ml) is added. The solution of 4-hydroxycyclohexylglycine(see Coll. Czech. Chem. Comm. 49, 712-742 (1984)) is cooled to 0° C. andtreated with triethylamine (11.37 ml) and 4-methoxybenzenesulfonylchloride (10.95 g). The reaction mixture is allowed to warm to roomtemperature and stirred over the weekend. The dioxane is removed invacuo and the remaining aqueous solution is diluted with 1Nhydrochloride acid. The resulting precipitate is collected, washed withwater and ether to yield(R)-N-(4-methoxybenzenesulfonyl)-4-hydroxycyclohexylglycine which isconverted to the methyl ester with methanol in the presence of thionylchloride. To a solution of(R)-N-(4-methoxybenzenesulfonyl-4-hydroxycyclohexylglycine methyl ester(0.859 g) in methylene chloride (8 ml) are added acetic anhydride (2.26ml) and pyridine (3.90 ml). The reaction mixture is stirred at roomtemperature overnight, quenched with methanol, washed with 1Nhydrochloric acid and extracted with methylene chloride. The methylenechloride extract is dried over sodium sulfate and evaporated to drynessto yield (R)-N-(4-methoxybenzenesulfonyl)-4-acetyloxycyclohexylglycinemethyl ester. Heating with 3 NHCl at reflux for 24 hours yields(R)-N-(4-methoxybenzenesulfonyl)-4-hydroxycyclohexylglycine.

EXAMPLE 34

Prepared similarly to the previous examples are

(a)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(trans-4-dimethylaminocyclohexyl)acetamidehydrochloride, m.p. 138°-146° C.

The starting material is prepared as follows:

A solution of oxalyl chloride (1.25 g) in methylene chloride (30 ml) iscooled to -78° C. and dimethylsulfoxide (1.16 ml) is slowly added. Thereaction mixture is stirred at -78° C. for about 30 minutes and asolution of (R)-N-(4-methoxybenzenesulfonyl)-4-hydroxycyclohexylglycinemethyl ester (2.34 g) in methylene chloride (30 ml) is added dropwise.Stirring is continued for 30 minutes at -78° C. and then at 0° C. for 30minutes. The reaction mixture is again cooled to -78° C., triethylamine(7.3 ml) is added dropwise, and the reaction mixture is stirred at -78°C. for 30 minutes, allowed to warm to room temperature over an hour,diluted with methylene chloride, washed first with 1N hydrochloric acidand then brine. The organic layer is dried over sodium sulfate,evaporated to dryness, and the resulting product is purified by flashchromatography using 50-60% ethyl acetate in hexane to yield(R)-N-(4-methoxybenzenesulfonyl)-4-oxocyclohexylglycine methyl ester asa white solid. Treatment with benzyl bromide in DMF in the presence ofpotassium carbonate at room temperature yields(R)-N-(4-methoxybenzenesulfonyl)-N-benzyl-4-oxocyclohexylglycine methylester as an oil. The ketone (2.2 g) is dissolved in methylene chloride(3 ml) and isopropanol (60 ml). Molecular sieves (3A°, 1.5 g), sodiumcyanoborohydride (0.311 g), and ammonium acetate (3.81 g) are added. Thereaction mixture is stirred at room temperature overnight, filtered andevaporated to dryness. The residue is partitioned between water andmethylene chloride and the product extracted with methylene chloride.The resulting product is purified by flash chromatography usingmethanol/methylene chloride/0.5% ammonium hydroxide as eluent to yield(R)-N-(4-methoxybenzenesulfonyl)-N-benzyl-4-aminocyclohexylglycinemethyl ester. N-Methylation with formic acid/formaldehyde/sodium formateat reflux temperature followed by hydrolysis with 3N hydrochloric acidat reflux temperature yields2-(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(tran-4-dimethylaminocyclohexyl)-aceticacid.

EXAMPLE 35

A solution ofN-benzyloxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-hydroxy-4-methylpentanamide(125 mg) in ethanol (100 ml) is hydrogenated in the presence of 5%palladium on charcoal (100 mg) at room temperature and atmosphericpressure to yieldN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-hydroxy-4-methyl-pentanamide,m.p. 81°-82° C.

The starting material is prepared as follows:

(R)-3-hydroxy-4-methyl-2-amino pentanoic acid methyl ester, preparedaccording to methodology described by Evans in Tetrahedron Letters 28,39 (1987) and J. Am. Chem. Soc. 109, 7151 (1981) from isobutyraldehyde,is converted, according to methodology in previous examples, to2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]3-hydroxy-4-methylpentanoicacid.

A solution of2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]3-hydroxy-4-methylpentanoicacid (1.4 g) in methylene chloride (3.5 ml) is treated with 2,6-lutidine(1.21 ml) and tert-butyl-dimethylsilyl trifluoromethanesulfonate (2.03ml) at 0° C. The solution is stirred at 0° C. for 4 hours, then at roomtemperature for 2 hours, poured into sodium bicarbonate solution (10.0ml) and extracted with ether. The resulting product is purified bycolumn chromatography on silica gel using gradients of ethylacetate/hexane as eluent to obtain2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]3-(tert-butyl-dimethylsilyloxy)-4-methylpentanoicacid tert-butyl-dimethylsilyl ester. Treatment of the ester (1.2 g) withpotassium carbonate (285 mg) in THF water (1:1) for 30 minutes at 0°under nitrogen, acidification and extraction with ethyl acetate yields2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]3-(tert-butyl-dimethylsilyloxy)-4-methylpentanoicacid.

To a solution of2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-(tert-butyl-dimethylsilyloxy)-4-methylpentanoicacid (0.5 g) in methylene chloride (10 ml) are addedO-benzylhydroxylamine hydrochloride (0.154 g),1-hydroxy-pyridobenzotriazole (HOPT, 0.131 g), N-methylmorpholine (0.371ml) at room temperature. Then1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (0.370 g) is added at 0°C. and the reaction mixture is stirred at room temperature overnightunder nitrogen. The reaction mixture is diluted with ethyl acetate andwater, and the ethyl acetate extract is washed with 1N hydrochloricacid, sodium bicarbonate solution, water and brine. The organic phase isdried, evaporated to dryness and the resulting product is purified byflash chromatography using ethyl acetate/hexane gradients as eluent toyieldN-benzyloxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-tert-butyl-dimethylsilyloxy)4-methylpentanamide.

A solution of the above (0.4 g) in acetonitrile (6.4 ml) is treated with48% hydrogen fluoride (0.25 ml) and stirred at room temperature for 4hours. Workup in the usual manner and purification by chromatography onsilica gel with ethyl acetate/hexane gradients as eluent yieldsN-benzyloxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-hydroxy-4-methylpentanamideas an oil.

Similarly prepared are

(a)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(n-propyl)amino]-3-hydroxypentanamide,m.p. 129°-131° C.;

(b)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(n-propyl)-amino]3-hydroxy-4-methylpentanamide,m.p. 69°-71° C.;

(c)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-3-hydroxy-4-methypentanamide,m.p. 81°-82° C.;

(d)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(n-propyl)amino]-3-hydroxyoctanamide,m.p. 123°-125° C.;

(e)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(n-propyl)amino]-3-hydroxy-5-methylhexanamide,m.p. 97°-99° C.

EXAMPLE 36

Similarly prepared to the previous examples are:

(a) N-hydroxy-2(R)-[(3-fluoro-4-methoxybenzenesulfonyl)(3-picolyl)amino]-3-methyl butanamide hydrochloride, [α]_(D) ²⁵ +33.85(c 10.39 mg/ml, CH₃ OH);

(b)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(2-tetrahydrofuranyl)acetamide, m.p. 89°-92° C., [α]_(D) ²⁵ +4.82 (c 8, CH₃ OH).

The starting material, R-(2-tetrahydrofuranyl)-glycine, is preparedaccording to J. Am. Chem. Soc. 110, 1547 (1988).

(c)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(3-picolyl)amino]-2-(2-tetrahydrofuranyl)-acetamide,m.p. 91°-93° C., [α]_(D) ²⁵ +0.62 (c 7.0, CH₃ OH);

(d)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(2-tetrahydrofuranyl)-acetamide,m.p. 143°-144° C.; [α]_(D) ²⁵ +1.03 (c 6.4, CH₃ OH);

(e)N-hydroxy-2(S)-[(4-methoxybenzenesulfonyl)(3-picolyl)amino]-2-(2-tetrahydrofuranyl)-acetamide,m.p. 162°-163° C.; [α]_(D) ²⁵ -4.22 (c 6.5, CH₃ OH);

(f)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-cyclopentylacetamidehydrochloride, m.p. >140° dec.; [α]_(D) ²⁵ +27.9 (c 9.4, CH₃ OH);

(g)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(trans-4-hydroxy-2-tetrahydrofuranyl)acetamide,m.p. 53°-56° C., as a mixture of diastereoisomers; the startingmaterial, trans-(4-hydroxy-2-tetrahydrofuranyl)glycine is preparedaccording to J. Am. Chem. Soc. 110, 4533 (1988);

(h)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(4-oxacyclooctyl)acetamide,m.p. 152°-157° C., as a mixture of diastereoisomers;

(i)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)-amino]-2-(4-oxacycloheptyl)acetamidehydrochloride, m.p. 130°-145° C., as a mixture of diastereoisomers;

(j)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-cyclooctylacetamidehydrochloride, m.p. 124°-140° C.;

(k)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(2-oxohexahydroazepin-5-yl)acetamidehydrochloride, diastereoisomer A, m.p. 160°-172° C. dec.

(l)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(2-oxohexahydroazepin-5-yl)acetamidehydrochloride, diastereoisomer B, m.p. 155°-170° C.;

(m)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(2-oxohexahydroazeopin-5-yl)acetamide,diastereoisomer A, m.p. 115°-130° C.;

(n)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(2-oxohexahydroazepin-5-yl)acetamide,diastereoisomer B, m.p. 120°-140° C.;

(o)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(n-propyl)amino]-3,4-dimethoxybutanamide,m.p. 53°-55° C.;

(p)N-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(n-propyl)amino]-3-methoxy-3-(N-tert-butoxycarbonyl-4-piperidyl)propionamide,m.p. 102°-103° C.;

(q)N-hydroxy-4-[(4-methoxybenzenesulfonyl)(benzyl)amino]-N-(methoxycarbonylmethyl)-piperidine-4-carboxamidehydrochloride, m.p. 183.5°-185° C.;

(r)N-benzyloxy-4-[(4-methoxybenzenesulfonyl)(n-benzyl)amino]-N-(methoxycarbonylmethyl)-piperidine-4-carboxamide,m.p. 52.5°-55° C.

(s)N-hydroxy-2-[[4-methoxybenzensulfonyl](benzyl)amino]-2-[2-thienylthio)methyl]acetamideby starting the synthesis with β-(2-thienylthio)alanine (preparedaccording to the procedure of J. Am. Chem. Soc. 110, 2237, (1988).

(t)N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-furanylthio)methyl]-acetamideby starting the synthesis with β-(2-furanylthio)alanine (preparedaccording to the procedure of J. Am. Chem. Soc. 110, 2237 (1988).

(u)N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(phenylthio)-methyl]acetamideby starting the synthesis with β-(phenylthio)alanine (prepared accordingto the procedure of J. Am. Chem. Soc. 110, 2237 (1988).

EXAMPLE 37

Preparation of 3000 capsules each containing 25 mg of the activeingredient, for example,N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-3-methylbutanamidehydrochloride:

    ______________________________________                                        Active ingredient    75.00 g                                                  Lactose             750.00 g                                                  Avicel PH 102       300.00 g                                                  (microcrystalline cellulose)                                                  Polyplasdone XL      30.00 g                                                  (polyvinylpyrrolidone)                                                        Purified water      q.s.                                                      Magnesium stearate   9.00 g                                                   ______________________________________                                    

The active ingredient is passed through a No. 30 hand screen.

The active ingredient, lactose, Avicel PH 102 and Polyplasdone XL areblended for 15 minutes in a mixer. The blend is granulated withsufficient water (about 500 mL), dried in an oven at 35° C. overnight,and passed through a No. 20 screen.

Magnesium stearate is passed through a No. 20 screen, added to thegranulation mixture, and the mixture is blended for 5 minutes in amixer. The blend is encapsulated in No. 0 hard gelatin capsules eachcontaining an amount of the blend equivalent to 25 mg of the activeingredient.

What is claimed is:
 1. A compound of formula I ##STR13## wherein Ar iscarbocyclic or heterocyclic aryl;R is hydrogen, lower alkyl, carbocyclicaryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl,biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- orpoly-halo-lower alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₇ -cycloalkyl-loweralkyl, (oxa or thia)-C₃ -C₆ -cycloalkyl, (oxa or thia)-C₃ -C₆-cycloalkyl]-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl,lower alkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-loweralkyl, (amino, mono- or di-lower alkylamino)-lower alkyl,acylamino-lower alkyl, (N-lower alkyl-piperazino or N-carbocyclic orheterocyclic aryl-lower alkylpiperazino)-lower alkyl, or (morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl or N-loweralkylpiperidyl)-lower alkyl; R₁ is hydrogen, lower alkyl, carbocyclicaryl-lower alkyl, carbocyclic aryl, heterocyclic aryl, biaryl,biaryl-lower alkyl, heterocyclic aryl-lower alkyl, mono- orpoly-halo-lower alkyl, C₃ -C₁₀ -cycloalkyl, C₃ -C₇ -cycloalkyl-loweralkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-loweralkyl, (carbocyclic or heterocyclic aryl)-lower alkoxy-lower alkyl,lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- ordi-lower alkylamino)-lower alkyl, (N-lower alkyl-piperazino orN-carbocyclic or heterocyclic aryl-lower alkylpiperazino)-lower alkyl,(morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, N-acylor N-lower alkylpiperidyl)-lower alkyl, acylamino-lower alkyl,piperidyl, (morpholino, thiomorpholino, piperidino, pyrrolidino,piperidyl, N-acyl or N-lower alkylpiperidyl)-(hydroxy or lower alkoxy)lower alkyl, pyrrolidinyl, hexahydroazepinyl, N-lower alkyl orN-acyl(hexahydroazepinyl, piperidyl or pyrrolidinyl), C₅ -C₁₀-oxacycloalkyl, C₅ -C₁₀ -thiacycloalkyl, (hydroxy-or oxo-) C₅ -C₁₀-cycloalkyl, (hydroxy- or oxo-) C₅ -C₁₀ -thiacycloalkyl, (hydroxy- oroxo-) C₅ -C₁₀ -oxacycloalkyl, (amino, mono- or dialkylamino oracylamino)-C₅ -C₁₀ -cycloalkyl, 2-oxo(pyrrolidinyl, piperidyl orhexahydroazepinyl); (carbocyclic or heterocyclic aryl)-(thio, sulfinylor sulfonyl)-lower alkyl; R₂ is hydrogen or lower alkyl; or apharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 of formula Iwherein Ar is phenyl which is unsubstituted ormono-, di- or wi-substituted by C₁ -C₇ -alkoxy, hydroxy, phenyl-loweralkoxy, C₃ -C₇ -cycloalkyl-lower alkoxy, lower alkyloxy-lower alkoxy,halogen, lower alkyl, cyano, nitro, trifluoromethyl, loweralkyl-(sulfinyl or sulfonyl), amino, mono- or di-lower alkylamino or, onadjacent carbon atoms, by C₁ -C₂ -alkylenedioxy or oxy-C₂ -C₃ -alkylene;or Ar is thienyl, isoxazolyl or thiazolyl each of which is unsubstitutedor mono- or di-substituted by lower alkyl; R is hydrogen; lower alkyl,phenyl-lower alkyl; phenyl which is unsubstituted or mono-, di- ortri-substituted by lower alkoxy, hydroxy, halogen, lower alkyl,trifluoromethyl, or, on adjacent carbon atoms, by C₁ -C₂ -alkylenedioxyor oxy-C₂ -C₃ -alkylene; a heterocyclic aryl radical selected frompyridyl, thiazolyl and quinolinyl, each unsubstituted or mono- ordisubstituted by lower alkyl; biphenylyl; biphenylyl-lower alkyl;(pyridyl or thienyl)-lower alkyl; trifluoromethyl; C₃ -C₇ -cycloalkyl,C₃ -C₇ -cycloalkyl-lower alkyl; (oxa or thia)-C₃ -C₆ -cycloalkyl, [(oxaor thia)-C₃ -C₆ -cycloalkyl]-lower alkyl; hydroxy-lower alkyl; (N-loweralkyl-piperazino or N-phenyl-lower alkylpiperazino)-lower alkyl or(morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl orN-lower alkylpiperidyl)-lower alkyl; R₁ is hydrogen; lower alkyl;phenyl-lower alkyl wherein phenyl is unsubstituted or substituted bylower alkyl, lower alkoxy, halogen, trifluoromethyl or, on adjacentcarbon atoms, by C₁ -C₂ -alkylenedioxy; biphenylyl-lower alkyl;heterocyclic aryl-lower alkyl wherein heterocyclic aryl is selected fromthiazolyl, pyrazolyl, pyridyl, imidazolyl and tetrazolyl eachunsubstituted or substituted by lower alkyl; C₃ -C₁₀ -cycloalkyl; C₃ -C₇-cycloalkyl-lower alkyl; hydroxy-lower alkyl, (phenyl or pyridyl)-loweralkoxy-lower alkyl; lower alkyl-(thio, sulfinyl or sulfonyl)-loweralkyl; (amino, mono- or di-lower alkylamino)-lower alkyl; (N-loweralkyl-piperazino or N-phenyl-lower alkylpiperazino)-lower alkyl;(morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl orN-lower alkylpiperidyl)-lower alkyl; lower alkanoylamino-lower alkyl; R₃-CONH-lower alkyl wherein R₃ represents (di-lower alkylamino, N-loweralkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino orN-alkylpiperidyl)-lower alkyl; piperidyl; pyrrolidinyl;hexahydroazepinyl; N-lower alkyl- or N-acyl-(hexahydroazepinyl,piperidyl or pyrrolidinyl); C₅ -C₁₀ -oxacycloalkyl; C₅ -C₁₀-thiacycloalkyl; (hydroxy- or oxo-) C₅ -C₁₀ -cycloalkyl; (hydroxy- oroxo-) C₅ -C₁₀ -thiacycloalkyl; (hydroxy- or oxo-) oxacycloalkyl; (amino,mono- or dialkylamino or lower alkanoylamino)-C₅ -C₁₀ -cycloalkyl;phenyl-thio-lower alkyl wherein phenyl is unsubstituted or substitutedby lower alkyl, lower alkoxy, halogen, trifluoromethyl, or, on adjacentcarbon atoms, by C₁ -C₂ -alkylenedioxy or oxy-C₂ -C₃ -alkylene;heterocyclic aryl-thio-lower alkyl wherein heterocyclic aryl is selectedfrom thiazolyl, pyrazolyl, pyridyl, imidazolyl, thienyl and furanyl,each unsubstituted or substituted by lower alkyl; R₂ is hydrogen orlower alkyl.
 3. A compound according to claim 1 of formula II ##STR14##wherein R is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl,carbocyclic aryl, heterocyclic aryl, biaryl, biaryl-lower alkyl,heterocyclic aryl-lower alkyl, mono- or poly-halo-lower alkyl, C₃ -C₇-cycloalkyl, C₃ -C₇ -cycloalkyl-lower alkyl, (oxa or thia)-C₃ -C₆-cycloalkyl, [(oxa or thia)-C₃ -C₆ -cycloalkyl]-lower alkyl,hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl,lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, (amino, mono- ordi-lower alkylamino)-lower alkyl, acylamino-lower alkyl, (N-loweralkyl-piperazino or N-carbocyclic or heterocyclic aryl-loweralkylpiperazino)-lower alkyl, or (morpholino, thiomorpholino,piperidino, pyrrolidino or N-lower alkylpiperidyl)-lower alkyl;R₁ ishydrogen, lower alkyl, carbocyclic aryl-lower alkyl, carbocyclic aryl,heterocyclic aryl, biaryl, biaryl-lower alkyl, heterocyclic aryl-loweralkyl, mono- or poly-halo-lower alkyl, C₅ -C₈ -cycloalkyl, C₅ -C₇-cycloalkyl-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, loweralkoxy-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-loweralkyl, (amino, mono-or di-lower alkylamino)-lower alkyl, (N-loweralkyl-piperazino or N-carbocyclic or heterocyclic aryl-loweralkylpiperazino)-lower alkyl, (morpholino, thiomorpholino, piperidino,pyrrolidino, piperidyl or N-lower alkylpiperidyl)-lower alkyl,piperidyl, N-lower alkylpiperidyl, or acylamino-lower alkyl representedby R₃ -CONH-lower alkyl, pyrrolidinyl, hexahydroazepinyl or N-loweralkyl (pyrrolidinyl or hexahydroazepinyl), C₅ -C₇ -oxacycloalkyl, C₅ -C₇-thiacycloalkyl, hydroxy or oxo-cyclohexyl, (amino, mono- or di-loweralkylamino) cyclohexyl or 2-oxohexahydroazepinyl; phenyl-thio-loweralkyl wherein phenyl is unsubstituted or substituted by lower alkyl;heterocyclic aryl-thio-lower alkyl wherein heterocyclic aryl is selectedfrom thienyl and furanyl, each unsubstituted or substituted by loweralkyl; R₂ is hydrogen; R₃ in R₃ -CONH-lower alkyl is lower alkyl,carbocyclic or heterocyclic aryl, di-lower alkylamino, N-loweralkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino,N-alkylpiperidyl, or (di-lower alkylamino, N-lower alkylpiperazino,morpholino, thiomorpholino, piperidino, pyrrolidino, pyridyl or N-loweralkylpiperidyl)-lower alkyl; R₄ is hydrogen, lower alkoxy, hydroxy,carbocyclic or heterocyclic aryl-lower alkoxy, lower alkylthio orcarbocyclic or heterocyclic aryl-lower alkylthio, lower alkyloxy-loweralkoxy, halogen, trifluoromethyl, lower alkyl, nitro or cyano; R₅ ishydrogen, lower alkyl or halogen; or R₄ and R₅ together on adjacentcarbon atoms represent methylenedioxy, ethylenedioxy, oxyethylene oroxypropylene; or a pharmaceutically acceptable prodrug derivativethereof; or a pharmaceutically acceptable salt thereof.
 4. A compoundaccording to claim 1 of formula III ##STR15## wherein R represents loweralkyl, trifluoromethyl, C₅ -C₇ -cycloalkyl, (oxa or thia)-C₄ -C₅-cycloalkyl, biaryl, carbocyclic monocyclic aryl or heterocyclicmonocyclic aryl; R₁ represents hydrogen, lower alkyl, C₅ -C₈-cycloalkyl, monocyclic carbocyclic aryl, carbocyclic aryl-lower alkyl,heterocyclic aryl-lower alkyl, lower alkoxy-lower alkyl, hydroxy-loweralkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, di-loweralkylamino-lower alkyl, (N-lower alkylpiperazino, morpholino,thiomorpholino, piperidino or pyrrolidino)-lower alkyl, C₅ -C₇-oxacycloalkyl, (hydroxy, oxo or di-lower alkylamino) cyclohexyl, R₃-CONH-lower alkyl, phenyl-thio-lower alkyl wherein phenyl isunsubstituted or substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl, heterocyclic aryl-thio-lower alkyl wherein heterocyclicaryl is selected from thiazolyl, pyrazolyl, pyridyl, imidazolyl, thienyland furanyl, each unsubstituted or substituted by lower alkyl; R₃represents lower alkyl, carbocyclic aryl, heterocyclic aryl, di-loweralkylamino, N-lower alkylpiperazino, morpholino, thiomorpholino,piperidino, pyrrolidino, N-alkylpiperidyl, or (di-lower alkylamino,N-lower alkylpiperazino, morpholino, thiomorpholino, piperidino,pyrrolidino or N-alkylpiperidyl)-lower alkyl; R₄ represents lower alkoxyor carbocyclic or heterocyclic aryl-lower alkoxy; or a pharmaceuticallyacceptable prodrug derivative thereof; or a pharmaceutically acceptablesalt thereof.
 5. A compound according to claim 4 of formula III whereinR represents monocyclic carbocyclic aryl or monocyclic heterocyclicaryl; R₁ and R₄ have meaning as defined in said claim; or apharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 4 of formula III wherein R represents heterocyclic monocyclic arylselected from tetrazolyl, triazolyl, thiazolyl, imidazolyl and pyridyl,each unsubstituted or substituted by lower alkyl; or R represents phenylor phenyl substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R₁ represents lower alkyl, cyclohexyl, 2- or3-tetrahydrofuranyl, or R₃ -CONH-lower alkyl wherein R₃ represents(di-lower alkylamino, N-lower alkylpiperazino, morpholino,thiomorpholino, piperidino, pyrrolidino or N-alkylpiperidyl)-loweralkyl; and R₄ represents lower alkoxy or phenyl-lower alkoxy; or apharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 4 of formula III wherein R represents 2-, 3- or 4-pyridyl orphenyl; R₁ represents C₁ -C₄ -alkyl, cyclohexyl, 2- or3-tetrahydrofuranyl, (phenyl-, thienyl- or furanyl-)thiomethyl, or R₃--CONH--C₁ -C₄ -alkyl wherein R₃ represents di-C₁ -C₄ -alkylamino-C₁ -C₄-lower alkyl: and R₄ represents lower alkoxy; or a pharmaceuticallyacceptable prodrag derivative thereof; or a pharmaceutically acceptablesalt thereof.
 8. A compound according to claim 4 of formula III whereinR represents 3-pyridyl or 4-pyridyl; R₁ represents isopropyl, cyclohexylor 2-tetrahydrofuranyl; and R₄ represents lower alkoxy; or apharmaceutically acceptable prodrug derivative thereof; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 4 wherein the asymmetric carbon to which R₁ is attached isassigned the (R)-configuration.
 10. A compound according to claim 4which isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamideor a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 4 which isN-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](4-picolyl)amino]-2-cyclohexylacetamideor a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 4 which isN-hydroxy-2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(2-tetrahydrofuranyl)acetamide or a pharmaceutically acceptable salt thereof.
 13. Amatrix-degrading metalloproteinase inhibiting pharmaceutical compositioncomprising an effective matrix-degrading metalloproteinase inhibitingamount of a compound of claim 1 in combination with one or morepharmaceutically acceptable carriers.
 14. A method of inhibitingstromelysin or collagenase activity in mammals which comprisesadministering to a mammal in need thereof an effective stromelysin orcollagenase inhibiting amount of a compound of claim
 1. 15. A method oftreating matrix-degrading metalloproteinase dependent conditions inmammals which comprises administering to a mammal in need thereof aneffective matrix-degrading metalloproteinase inhibiting amount of acompound of claim
 1. 16. A compound according to claim 4 of Formula IIIwherein R represents pyridyl, pyridyl substituted by lower alkyl,phenyl, or phenyl substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl; R₁ represents (phenyl-,thienyl- or furanyl-) thio-C₁-C₄ -alkyl; and R₄ represents lower alkoxy; or a pharmaceuticallyacceptable prodrug derivative thereof; or a pharmaceutically acceptablesalt thereof.
 17. A compound according to claim 4 of Formula III whereinR represents phenyl or phenyl substituted by lower akyl, lower alkoxy,halogen or trifluoromethyl; R₁ represents (phenyl)-thiomethyl,(2-thienyl)-thiomethyl or (2-furanyl)-thiomethyl; and R₄ representslower alkoxy; or a pharmaceutically acceptable prodrug derivativethereof; or a pharmaceutically acceptable salt thereof.